SU472506A3 - Method for producing morpholine derivatives - Google Patents

Description

where Ri, R2, Hz, R4, RS, Xb have the same or different meanings and represent hydrogen or alkyl radicals having up to 3 carbon atoms; Re is hydrogen, alkyl or alkenyl having up to 6 carbon atoms, cycloalkyl having up to 5 carbon atoms; X is phenyl or naphthyl, unsubstituted or substituted by one or more halogen atoms, alkyl, alkoxy or alkylthio radicals, each of which contains up to 10 carbon atoms, by haloalkyl or haloalkoxy, each of which contains up to 5 carbon atoms, by alkenyl, alkenylOXY- , alkynyloxy, cycloalkoxy, 15 cycloalkyl, each of which contains up to 10 carbon atoms, aryl, aryloxy, alkylaryloxy, aralkyl or aralkoxy radicals, each of which has up to 10 carbon atoms, alkyl having up to 20 5 carbon atoms and p-substituted alkoxy having up to 5 carbon atoms, alkanoyl having up to 6 carbon atoms, hydroxy or methylenedioxy, alkylene having 3-4 carbon atoms. The method consists in that the compound of the general formula X-OH, where X has the above values, is reacted with the morpholine of the general formula f) ZCR ,, -Y RI N where Ri-Re has the values indicated; Z is a halogen atom or sulphonyloxy-40 soil. The process is conducted in the medium of a solvent or diluent, for example, dimethylformamide, dimethylsulfoxinda, dioxane, dimethoxyethane, in the presence of a strong base, 45 such as alkali metal or its amide or hydride, preferably at a temperature of about 150 ° C. Products are isolated or salified in a manner known per se. Suitable salts 50 are hydrochloride, gluconate, salicylate, citrate, asborate, benzoate, a-naphthoate, adipate, 1,1-methylenebis; (2-hydroxy-3-naphthoate), or with a sulfonated polystyrene resin. Example 1. A solution of 4-benzyl-2-hydroxymethylmorpholine (2.07 g) in anhydrous carbon tetrachloride (20 ml) is added in canals with stirring to a solution of thionyl chloride (0.74 ml) in anhydrous four. 60 carbon chloride (15 ml) at a temperature of 0 ° C. The mixture was stirred and heated under reflux for 1 hour. Chloroform (50 ml) and aqueous 2N were then added. sodium hydroxide solution (50 ml), and 65 5 25 30 35 55 the mixture was stirred at room temperature for 30 minutes. The separated organic layer was washed with water (50 ml), dried and the solvent was removed by evaporation of the solution under reduced pressure. Received 5-benzyl-2-chloromethylene with t. Kip. 104 ° C (0.2 mmHg), which is additionally characterized as its acid oxalate; m.p. 146-148 ° C (after crystallization from ethyl acetate), 4-Benzyl-2-oxymethylmorpholine, used as a starting product, can be obtained by the following method. A mixture of allyl glycidyl ether (57 g) and benzylamine (107 g) is heated with stirring for 18 hours at a temperature of 140 ° C, and then an excess of isylamine is distilled off. The residue is distilled to give 1-allyloxy-3-benzylamine-2-nropanol with a bale. 150-152 ° C (1.5 mmHg). A mixture of this product (66.3 g) and triethylampa (42 ml) in anhydrous methylene chloride (150 ml) is cooled to 0 ° C and stirred, adding dropwise a solution of chloroacetochloride (22.8 ml) in anhydrous methylene chloride (50 ml ). This mixture was stirred at room temperature for 18 hours, washed with aqueous 2N. with a solution of hydrochloric acid (2 times 50 ml), then with water (50 ml), dried and the solvent was removed by evaporation at reduced pressure. N- (3-Allploxy-2-hydroxypronyl) benzylchloroacetamide is obtained as an oil. A solution of this oil in anhydrous methanol (50 ml) was added to a solution of sodium (7 g) in anhydrous methanol (500 ml) and the mixture was heated under stirring at reflux for 8 hours. The solvent was then evaporated under reduced pressure and the residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The separated aqueous layer was extracted with Egyl acetate (2 times but 100 ml) and the combined organic solutions were washed with water and dried; the solvent is evaporated under reduced pressure. The residue is distilled to give 2-allyloxymethyl-4-benzyl-morphon-5-one with m.p. 182-184 ° C (1.5 mm Hg. Art.). A solution of this product (26.1 g) in anhydrous ether (50 ml) is added dropwise to a stirred suspension of lithium aluminum tripe (5.7 g) in anhydrous ether (200 ml) at such a rate as to provide a slight boil for the mixture. This mixture is heated under stirring under reflux for 18 hours, then cooled with ice, simultaneously decomposing an excess of lithium aluminum hydride with the successive addition of water (5.7 ml), aqueous 2N. sodium hydroxide solution (5.7 ml) and water (17.1 ml). The mixture is stirred for 30 minutes, then filtered, and the solid residue is washed with reflux. The combined filtrates and wash water are dried and then the solvent is evaporated under reduced pressure. 2-allyloxymethyl-4-benzylmorphonone is obtained, which is characterized as acid oxalate with m.p. 118-119 ° C (after crystallization from acetone). A solution of 2-allyloxymethyl-4-benzylmorpholine (125 g) and anhydrous ether (100 ml) is added to a stirred solution of sodium (25 g) in liquid ammonia (1.5 l) and the mixture is heated under reflux with stirring for 4 hours. The excess sodium is destroyed by the addition of ammonium chloride (20 g) and ammonia is evaporated, skipping a stream of nitrogen. The residue was partitioned between ether (500 ml) and water (500 ml) and the separated aqueous layer was extracted with ether (2 times 250 ml). The combined ether solutions are dried and the ether is evaporated under reduced pressure. The residue is distilled to give 4-benzyl-2-hydroxymethylmorpholine with a m.p. 150-152 ° C (1 mm Hg. Art.). Example 2. The process described in Example 1 was repeated, except that an equivalent amount of the corresponding 4-substituted 2-hydroxymethylmorpholine was used as starting material. The compounds listed in Table 2 were obtained. 1. Table 2 H-CHj-lI-RS boiling point, C (. M mt. Art.) 76-78 (0.5) 120 (20) (i (20) 56-158 (20) t a b li and a 3 2

Formula ReNHa (60 ml), allyl glycidyl ether (50 g) and ethanol (500 ml) are heated under reflux for 3 hours and then evaporated to dryness under reduced pressure. The residue is distilled and the desired 1-alkyloxy-3-substituted amino-2-propanol is obtained. The boiling point of these compounds is shown in Table. 2

The process described in the second, third, and fourth parts of Example 1 was repeated using the compound of the above formula instead of 1-allyloxy-3-benzylamino-2-crocanol. The compounds obtained in series are given in Table. 3 and 4.

At measure 3, the process described in Example 1 was repeated, except that 4-benzyl-2-hydroxymethyl-6-methylmorpholine was used instead of 4-benzyl-2-hydroxymethylmorpholine. 4-benzyl-2-chloroethyl-6-methyl-morpholine was obtained with a boiling point of 130 ° C (1.6 mmHg).

4-benzyl-2-hydroxymethyl-6-morpholine used as a starting product can be obtained under the reaction conditions described in Example 1, except that a-chloropropionyl chloride is used instead of chloroacetic acid chloride. In this way, 2-allyloxymethyl4-benzyl-6-methylmorpholine was sequentially obtained with a bale. 135-150 ° C (0.6-1 mm Hg. Art.) And 4-benzyl-2-oxymethyl-6-methylmorpholine with t. Kip. 140-150 ° C (1 -1.2 mm Hg. Art.).

Example 4. A solution of 4-benzyl-2-hydroxymethylmorpholip (1.0 g) and toluenesulfonyl chloride (0.95 g) in a mixture of anhydrous acetone (30 ml) and triethylamine (2.4 ml) was stirred at room temperature for 4 hours, and then heated under reflux for 1 hour. The mixture was filtered and acetone was removed from the filtrate by evaporation under reduced pressure. The residual oil was dissolved in 50 ml of ether, the ethereal solution was washed three times with 20 ml of water, dried and evaporated to dryness under maintenance pressure. Got 4-B1 Zyl-2-toluene- / g - sulfonyloxymethylmorpholine in the form of oil.

EXAMPLE 5 A 50% dispersion of yatride hydride in mineral oil (0.96 g) was added to a stirred solution of o-oxyacetophenol (2.72 g) in anhydrous dimethylformamide (50 ml) and the mixture was stirred until the rapid evolution of gas ceased. To this mixture was added a solution of 4-benzyl-2-chloromethylmorpholine (4.5 g) in dimethylformamide (20 ml) and the mixture was heated with stirring for 18 hours at a temperature of 130-140 ° C. Then dimethylformamide was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 2N. hydrochloric acid (50 ml). The separated organic layer was extracted with 2N. hydrochloric acid (2 times in 30 ml each). The combined acidic extracts were washed with ether (50 ml), and then the hemmed, etched with aqueous Yun. sodium hydroxide solution. This solution was extracted with ethyl acetate (3 x 50 ml) and the combined extracts were washed with water (50 ml), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Got 2- (o-acetylphenoxymethyl | - 4-bepzilmorpholine - acid oxalate; t.nl. 181 - 184 ° C (after recrystallization from acetone).

A solution of this oxalate (1.2 g) in a mixture of ethyl alcohol, denatured with methyl alcohol (45 ml), with water (5 ml) was shaken with hydrogen at ambient temperature and atmospheric pressure, in the presence of a catalyst as 5% palladium on charcoal (0.3 g) until hydrogen absorption is complete. Then the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and methanol to give acid oxalate 2-fo-acetyl-phenoxymethyl) - morpholine Art. square 151 - 153 ° С (decomposition).

Example 6. A 50% dispersion of sodium hydride in mineral oil (0.24 g) was added to a stirred solution of o-ethoxyphenol (0.7 g) in anhydrous dimethylformamide

(30 ml) and the mixture was stirred until the rapid evolution of gases ceased. After successive addition of a solution of 4-benzyl-2-chloromethylmorpholine (1.1 g) in anhydrous dimethylformamide (30 ml) and then potassium iodide (0.8 g), the mixture was heated with stirring for 64 hours at a temperature of 130-140 ° C. The product was isolated as described in Example 5 and obtained 4-benzyl-2- (o-ethoxyphenoxymethyl) -morpholine, which was characterized as acid oxalate, mp. 170-172 ° C (after crystallization from methanol).

Example 7. The process described in the example.

6, was repeated, except that anhydrous dimethyl sulfoxide was used instead of dimethylformamide, and the reaction was carried out at 100 ° C for 18 hours under a nitrogen atmosphere. The cooled reaction mixture was diluted with 2 p. Hydrochloric acid and washed with ether (3 times 50 ml each time). The acidic solution was basified with aqueous 11 n. sodium hydroxide solution and extracted with ether (3 times 50 ml each time). United essential extracts

washed with water (50 ml) and dried. The ether was evaporated under reduced pressure. 4-benzyl-2- (o-ethoxyfenoxymethyl) -morpholine was obtained as acid oxalate; m.p. 170-172 ° C (after crystallization from methanol).

Example 8. The process described in Example 7 was repeated, except that 5benzyloxy-2-ethoxyphenol (1.2 g), sodium hydride 50% dispersion in mineral oil was used as starting products.

(0.24 g), potassium iodide (0.8 g) and 4-benzyl-2 chloromethylmorpholine (1.1 g) in 50 ml of anhydrous dimethyl sulfoxide. 4-benzyl-2- (5-benzyloxy-2-ethoxyphenoxymethyl) morpholine was obtained, which was used without further purification.

A solution of this product in ethanol (80 ml) was agitated under a hydrogen atmosphere at room temperature and atmospheric pressure in the presence of 5% palladium on carbon in

as a catalyst (0.5 g) until the absorption of hydrogen ceases. Then the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate and GETTED 2- (2ethoxy-5-hydroxyphenoxymethyl) -morpholine with m.p. 142-144 ° C (new product).

5-Benzyloxy-2-ethoxyphenol, used as a starting product, can be obtained as follows.

A solution of 4-benzyloxyphenol (30 g) in benzoyl peroxide (51.9 g, containing 30% by weight of water in chloroform (750 ml), was heated under reflux for 6 hours. The cooled mixture was washed with saturated

an aqueous solution of sodium bicarbonate (6 times 200 ml), dried over anhydrous magnesium sulphate, evaporated to dryness under reduced pressure. The residue was shifted with carbon tetrachloride (50 ml), the mixture was filtered and crystallized from ethyl acetate. 4-benzoxy-2-hydroxyphenyl 11-ooate with m.p. 174-17b ° C.

To a solution of this product (6.4 g) in anhydrous tetrahydrofuran (50 ml) was added dihydrofuran (10 ml) and toluene-p-sulfonic acid (0.05 g) and the mixture was stirred at room temperature for 18 hours. After adding ether (100 ml), the mixture was washed with a saturated aqueous solution of sodium bicarbonate (3 times 50 ml), dried and evaporated to dryness under reduced pressure. The residue was crystallized from ethanol to obtain 4-benzyloxy-2- (tetrahydropyran-2-yloxn) phenylbeisoate with m.p. 98-99 ° C.

This product (7.2 g) was dissolved in a solution of sodium (0.5 g) in ethanol (100 ml) and the mixture was heated with stirring at reflux for 1 hour. Ethyl iodide (10 ml) was then added and the mixture was again heated by stirring at reflux for 2 hours. After evaporation of ethanol under reduced pressure, the resulting residue was distributed between 2 p hydrochloric acid (100 ml) and ether (100 ml). The acidic solution was extracted with ether (2 times 50 ml) and the combined ethereal solutions were extracted with aqueous 2N. sodium hydroxide solution (3 times but 50 ml). The combined ether extracts were dried and evaporated to dryness. The residue was dissolved in toluene (20 ml) and the Florisil (80 g) was chromatographed on a silica gel column. The column was eluted with toluene (1 l) and the eluate was evaporated to dryness, the residue was crystallized from a mixture of petroleum ether (T. nl. 40-60 ° C) and ether and received 5-benzyloxy-2-ethoxyphenol with T. pl. 65-67 ° C.

Example 9. The process described in Example 7 was repeated, except that the corresponding products used were the corresponding phenol and the corresponding 4-substituted 2-chloromethylmorpholine. The compounds listed in Table 2 were obtained. five.

Example 10. The compound described in example 6, and some of the compounds listed in table. 5, when R is benzyl, is subjected to hydrogenolysis with hydrogen in the presence of palladium on carbon as a catalyst in the manner described in the second part of Example 8. The compounds obtained are listed in Table. 6

Example 11. A solution of 4-benzyl-2- (o-prop1-anylphenoxymethyl) -morpholine (2.1 g) and phenyl ester of chloroformic acid (1.0 ml) in anhydrous benzene (50 ml) was heated under reflux for 60 hour, and then evaporated to dryness under reduced pressure. The residue was dissolved in a solution of potassium hydroxide (6 g) in propanol (100 ml) and the mixture was heated under reflux for 48 hours, and then evaporated to dryness under a constant pressure. The residue was dissolved in 2 n. hydrochloric acid (100 ml)

and the solution was adjusted to pH 1 by adding dropwise concentrated hydrochloric acid. The acidic solution was extracted with ether (60 ml each time), the extracts were discarded, and the solution was acidified. The alkaline solution was extracted with ether and the ether extract was washed with water, dried and evaporated to dryness.

Obtained as a residue of 2- (o-prop-1anylphenoxymethyl) - morphone (a new product was characterized in the form of its oxalate; mp. 198-199 ° C after crystallization from a mixture of methanol and ethyl acetate).

The process described above was reiterated; . Received respectively 2- (o-allyloxyphenoxymethyl) -morpholine in the form of its acidic oxalate; m.p. 115-118 ° C (after crystallization from a mixture of ethanol and ether), and 2 (o-methylthiophepoxmethyl) -morpholine as

its acid oxalate; so nl 136-137 ° C (after crystallization from a mixture of methanol and ether).

EXAMPLE 12 A 60% dispersion of sodium hydride in mineral oil (1.6 g) was added to a stirred solution of o-ethoxyphenol (5.6 g) in anhydrous dimethylsulfoxnde (40 ml) and the mixture was stirred under nitrogen atmosphere until gases. A solution of 4benzyl-2-chloromethyl-6-methylmorpholine (4.8 g), in anhydrous dimethylsulfoxpd (10 ml) and potassium iodide (3.4 g) was added, and the mixture was heated with stirring under nitrogen atmosphere for 18 hours at 110 -120 ° C. The product was isolated as described in Example 7, and a mixture of two diasterioisomers 4benzyl-2- (o-ethoxphenoxymethylCH-6-methylmorpholine was obtained. This mixture of diasterioisomers was dissolved in

benzene (20 ml) and the solution was chromatographed on a silica gel column (120 g flornflower). The column was eluted with benzene (1200 ml) and the eluate was unary. The first isomer, (A) 4-benzyl-2- (o-ethoxyphenoxymethyl) -6-methylmorphol sc, was obtained as a residue. Then the column was eluted once more with a mixture of benzene and ethyl acetate (19: 1) by volume, and the eluate was evaporated to dryness. The second isomer (B) 4-benzyl-2- (o-ethoxyphenoxymethyl) -6-methylmorpholine was obtained as a residue.

Each of these isomers A and B was separately dissolved in ethanol (30 ml in each case) and the solutions were each separately stirred up with a catalyst in the form of 5% palladium on coal (0.5 g) in a hydrogen atmosphere at room temperature and atmospheric pressure to termination of hydrogen absorption. The mixture was purified, evaporated to dryness and the residues were characterized in the form of oxalates.

which were previously crystallized from X-OCHNg-T 1

11L

Benzyl

Methyl

Isopropyl

ilAllil Same

Cyclopentne

Cyclopentyl

Also

Note. Means new connection.

472506

Table 5

ABOUT

I r

Temperature

Melting salts, -C

179-181

dehydrated oxalate

161-162

Kisly) oxalate

205-207

Thats ive

158-159

171-172; 93

ioluhidrat 92

154-155; 152 151-152

dehydrated oxalate, hemihydrate

153-154; 150

Sour Oxalate

149 Same hemihydrate

149-150 136-137 180-181 112-113 100-101 145-146

Hydrochloride 159-161 105-107

Sour oxalate 155-157

Hlorgndrat 170-172

Hydrochloride 125-126

Sour oxalate 145-146

The same 112-113 128-130 141-142 185; 188

Hydrochloride, hemihydrate 213-214

Sour oxalate 125-127

Sour oxalate 143-144

The same 167-169 166-167 164-165 109-110

Sour oxalate 118-120 Same as 155-157

13

2-Ethoxyphenyl 2-Propnylphenyl

(2-1 Ipon-l-aHii l phenyl derivative used as starting product)

3-Methoxyfen 11L

2-indanyl

2-Diphenyl 11L

2-Benz11lfen11L

3-Fenox1 fen11L

2-1Dpclohexylfen11L

2-Mropoxy phenyl

(2-All-11-oxyphenyl-pro-1111 water used as the starting product)

2, b-Dnmeti lfeni l

2-sec-butylphenyl

2-Oks1 | fen11L

(2-benzyloxyphenyl derivative is used as the starting product)

Note. Mean new product.

mixtures of methanol and ether. Received dna ddnasterioisomer 2- (o-ethoxyfenoxymethyl) - 6methylmorpholine (new product). Sour oxalate of isomer A has m. Pl. 122-126 ° C (with decomposition); normal oxalate isomer B has so pl. PO-113 ° C (decomposition).

Example 13. A 60% dispersion of sodium hydride in mineral oil (0.8 g) was added to a stirred solution of o-ethoxyphenol (2.8 g) in anhydrous dimethyl sulfoxide (30 ml), and the mixture was stirred under a nitrogen atmosphere until the rapid release of gases. After adding a solution of 4-benzyl2-toluene-p-sulfonyloxymethylmorpholine (1.0 g) in anhydrous dimethyl sulfoxide (10 ml), the mixture was heated with stirring for 18 hours at 100 and 120 ° C. After cooling and diluting with water (100 ml), the aqueous solution was extracted three times with 50 ml of ether each time. The combined ether extracts were washed successively three times with 50 ml of 2N. an aqueous solution of sodium hydroxide and two times with 50 ml of water, then dried and evaporated to dryness under reduced pressure.

14

T a b l and c; i (i

t)

N 1 H

The salt

T. 11 l., -T

106-108

Acid oxalate 124-125 acid And semi-drad

159-161

Sour Oxalate

Oxalate 179-180

Sour oxalate 85-96

The same 141-143 132-133 129-130

Sour Oxalate

144-145 135-136

156-157

Got 4-benzyl-2- (o - ethoxyphenoxyimothyl) -morpholine, acid oxalate with so pl. 170-172 ° C (after crystallization from methanol).

Subject invention

1. The method of obtaining morpholine derivatives obsh, her formula

R,

-fr

.-r

R.N1 6

where Ri, R2, Hz, R4, Rs have the same or different meanings and represent hydrogen or alkyl radicals having up to 3 carbon atoms;

Re is hydrogen, alkyl or alkenyl having up to 6 carbon atoms, cycloalkyl, having up to 5 carbon atoms; X is phenyl or naphthyl, unsubstituted or substituted by one or more halogen atoms, alkyl, alkoxy or alkylthio radicals, each of which contains up to 10 carbon atoms, haloalkyl or haloalkoxy, each of which contains up to 5 carbon atoms, alkenyl, alkenyloxy, alkyloxy -, cycloalkoxy, cycloalkyl, each of which contains up to 10 carbon atoms, aryl, aryloxy, alkylaryloxy, aralkyl or aralkoxy radicals, each of which has up to 10 carbon atoms, alkyl having up to 5 carbon atoms and substituted alkoxy having up to 5 carbon atoms, alkanoyl having up to 6 carbon atoms, hydroxy- or methylenedioxygroup, alkylene having 3-4 carbon atoms; or salts thereof, characterized in that, in order to simplify the process, the compound of the general formula HON, where X has the above meaning, is reacted with the morpholine of the general formula IGR.R.j-RI N where Ri-Ro have the values indicated above; Z is a halogen atom, sulfonyloxygruzpa, followed by isolation of the products in free form or in the form of a salt by known prenems. 2. A method according to claim 1, characterized in that the process is conducted in a diluent or solvent medium. 3. A method according to claim 1, characterized in that the process is carried out at a temperature of about 150 ° C. 4. A method according to claim 1, characterized in that the process is carried out in the presence of a strong base.