FI72967B - FOERFARANDE FOER FRAMTAELLNING AV PHARMACEUTISKT AKTIVA 2-AMINO-3-BENZOYLFENYLACETAMIDDERIVAT. - Google Patents

Description

ΓΓ55Γ71 ....... ANNOUNCEMENT

Β 11 UTLÄGGININCSSKRIFT 72 96 7 • Jjg® C (45) Ι '-. Ϊ́:' 11 7:. hj (51) Kv.lk.4 / lnt.Cl.4 C 07 C 1 03/28, 103/76, C 07 D 295/18 FINLAND FINLAND (21) Patent application - Patenuniökning 803002 (22) Hakemiipilvi - Ansökningsdag 2 4 . 0 9.8 0 (23) Starting line - Giltighetxdag 24.09.8 0 (41) Become public - Blivit offentlig 2 ~ J 03 31

National Board of Patents and Registration Date of publication and publication. -

Patent and registration authorities V 'Ansökan utlagd och utl.skriften publicerad 30.04.87 (86) Kv. application - Int. trap (32) (33) (31) Privilege claimed - Begird priority 26 09.79 USA (US) 078860 (71) AH Robins Company, Incorporated, 1407 Cummings Drive, Richmond, Virginia, USA (72) James Robert Shanklin, Jr., Richmond, Virginia,

Dwight Allen Shamblee, Richmond, Virginia,

David Allan Walsh, Richmond, Virginia, USA (74) Berggren Oy Ab (54) Process for the preparation of pharmaceutically active 2-amino-3-benzoylphenylacetamide derivatives - For the preparation of pharmaceutically active 2-amino-3-benzoylphenylacetamides This invention relates to a process for the preparation of certain novel 2-amino-3-benzoyl-phenylacetamide derivatives.

These compounds can be used as anti-inflammatory agents, antipyretics, analgesics, and antiplatelet agents, and have very small gastric irritating side effects when administered orally to living animal bodies.

2-Amino-3-benzoylphenylacetic acids and their esters and metal salts having anti-inflammatory activity and antiplatelet properties are known from U.S. Patent 4,045,576.

South African Patent 68/4682 discloses benzoylphenylacetamides having various substituents at undefined positions on the phenyl ring. None of the specific compounds disclosed therein are aminophenylacetamides.

2,72967

In the past, strong anti-inflammatory drugs have generally been found to cause serious side effects such as gastric bleeding and wounds when administered orally to animals in an effective amount. The compounds of this invention have been found to have the advantage of being found to have an extremely low incidence of gastric irritation when administered in an amount effective to reduce inflammation compared to indomethacin and the less irritating 2-amino-3-benzoylphenylacetic acids known from the U3 patent. 4,045,576.

The present invention therefore relates to a process for the preparation of pharmaceutically active 2-amino-3-benzoylphenylacetamide derivatives of the formula R19 / CH, -C-N,

H: K

'Ύ ^ νη2 c = o where 12 ...

R and R are independently hydrogen or lower alkyl, or R and R together with the adjacent nitrogen atom form a morpholino group, X is hydrogen or halogen, and Y is hydrogen or halogen.

The term "lower alkyl" means straight and branched chain hydrocarbon groups having 1 to 6 carbon atoms and is exemplified by methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl and hexyl groups.

The term "halogen" means fluorine, chlorine, bromine and iodine atoms and is preferably a fluorine, chlorine or bromine atom.

3,72967

The compounds of formula I are prepared according to the invention by reducing a compound of formula 3 1

SR 0 R

y- ,, c = o 6- 12.

wherein R, R, X 1 and Y are as defined above and 3 R is phenyl or lower alkyl.

The following scheme illustrates the preparation of compounds of formula I.

O

3 M 12 + R SCH CNR R 1) t-BuOCl „

Hey 2 —Er „- * | ^ NH2 Formula III 3

C = 0 (n. -70 C

methylene chloride-Formula IV solution) Y SR3 I 9 1 2 ° CHCNRXRZ -C-NR1R2 * & £ 2 l_ (THF) y ^ NH2 I C = 0

Formula II Formula 1 4 72967 1 2 wherein R, R, R, X and Y have the same meaning as above.

The novel compounds of formula I have valuable pharmacological properties and are useful in administering them internally in an effective amount, relieving inflammation, relieving pain in an animal suffering from pain, preventing platelet aggregation and combating fever in living animals compared to other but very minor side effects. anti-inflammatory agents. A typical anti-inflammatory activity with minimal side effects is the compound of Example 3; namely, 2-amino-3- (4-chlorobenzoyl) -phenylacetamide, which has been found to have approximately the same potency as indomethacin, but which showed only about one hundredth as much stomach irritation as indomethacin.

Anti-inflammatory activity was demonstrated in laboratory animals using a modification of the method of the Evans-Blue Carrageenan Pleural Effusion Assay of Sancilio, L.F., J. Pharmacol. Exp. Ther. 168, 199-204 (1969).

The compounds of formula I have the ability to inhibit the accumulation of flakes in an experimental method presented by Born, J. of Phys. 162, 67-68 (1962) and Evans et al., J. of Expt. Med.

128, 877-894 (1968). The test drugs are administered to the rats, and after two hours, the rats are bled and flake-rich plasma is obtained. Collagen was added to the flake-rich plasma to cause flake accumulation and comparisons were made between control and treated samples.

The compounds of formula I also act as analgesics as determined by the bradykinin analgesia test method presented by Dickerson et al., Life Sci.

4, 2063-2069 (1965), modified by Sancilio and Cheung, Fed. Proc. 3j>, 774 (1976).

5,72967

The antipyretic activity of the compounds of formula I was demonstrated by the reduction of the febrile reaction in febrile animals without affecting the rectal temperature of normal temperature animals. The overtemperature reaction caused by subcutaneous injection of brewer's yeast into rats is eliminated by oral administration of a dose as low as 4-8 mg / kg of the compound of formula I and no significant change in the rectal temperature of normal temperature rats is observed.

Effective amounts of any of the above pharmacologically active compounds may be administered to a living animal body by any of a variety of routes, for example, orally such as capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. In preparing formulations, the active ingredient is incorporated into a suitable carrier, typically a pharmaceutical carrier. Suitable pharmaceutical carriers useful in the preparation of the preparations include starch, gelatin, glucose, magnesium carbonate, lactose, malt, etc. Liquid preparations can also be formed, and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerin, glycerin, glucose.

Pharmacologically active compounds can be advantageously used in unit doses of 0.1 to 250 mg or more, depending on the size of the animal. For example, a large animal such as a horse may require tablets containing 500-1000 mg of active ingredient. The unit dose may be administered in an appropriate amount per day, so that the daily dose may range from 0.3 to 450 mg.

5-25 mg proves to be optimal per unit dose.

It is only necessary that the active ingredient constitutes an effective amount, i.e., so that a suitable effective dose is obtained uniformly according to the dosage form employed. The exact 72967 individual doses as well as the daily doses will, of course, be determined in accordance with standard medical principles under the supervision of a physician or veterinarian.

Other pharmacologically active substances, buffers, acid-binding agents, etc. can be combined with the active substances for administration to the patient, and the amount of active substance in the preparations can be varied widely.

The preparation of intermediates of formula II is described in Preparation Methods 6-16. In general, these intermediates are prepared by first reacting the appropriate 2-aminobenzophenones with t-butyl hypochlorite and the appropriate thioacetamide in the cold (-60 to -70 ° C), followed by the addition of triethylamine.

Intermediates of formula II are reduced with Raney nickel to compounds of formula I in a solvent such as tetrahydrofuran and isolated by removal of the solvent and crystallization.

Preparation 1 (methylthioacetyl) -7-morpholine

A mixture of 40.2 g (0.3 mol) of ethyl methylthioacetate and 130 g (1.5 mol) of morpholine was refluxed for 70 hours.

7 72967

Distillation under reduced pressure gave 45 g (86%) of product, b.p. 104-105 ° C / 0.05 mm Hg by second distillation.

Analysis:

Calculated for CyH 2 NC 2 S: C, 47.98; H 7.48; N 7.99 experimentally: C 47.55; H 7.59; N 8.18

Preparation 2 2-Methylthio-N-methylacetamide

A mixture of 134 g (1.0 mol) of ethyl methylthioacetate and 310 g (10.0 mol) of methylamine was heated in a bomb at 150 ° C for 72 hours. Excess amine and ethanol produced were removed by distillation and the remaining thin syrup was distilled to give 112 g (94%) of the title compound as a colorless liquid, b.p. 76-78 ° C / 0.4 mm Hg.

Analysis:

Calculated for C 4 H 9 NOS: C, 40.31; H 7.61; N 11.75 Experimentally: C 39.78; H 7.69; N 11.88

Preparation 3 2-Methylthio-N, N-dimethylacetamide

A mixture of 134 g (1.0 mol) of ethyl methylthioacetate and 360 g (8.0 mol) of dimethylamine was heated in a bomb at 150 ° C for 10 hours. Excess amine and ethanol produced were removed by distillation and the residue was distilled to give 129 g (97%) of the title compound as a clear colorless liquid, b.p. 76-77 ° C / 0.5 mm Hg.

Analysis:

Calculated from C5H1; NOS: C 45.08; H 8.32; N 10.51 experimentally C 43.88; H 8.41; N 10.60

Preparation 4 2- (2-propylthio) acetamide

To a mixture of 46.7 g (0.5 mol) of 2-chloroacetamide in 200 ml of absolute ethyl alcohol was added slowly a solution of 38.1 g (0.5 mol) of 2-propanethiol in 100 ml of absolute ethyl alcohol. and 40 g of a 50% aqueous solution of sodium hydroxide. The mixture was refluxed for 1 hour and then filtered. The filtrate was concentrated under reduced pressure; the residue was dissolved in methylene chloride and the solution was dried over magnesium sulfate.

8 72967

The mixture was filtered and the filtrate was reconcentrated. On standing, the syrupy residue crystallized. Recrystallization from isopropyl ether gave 59.0 g (89%) of white flakes, melting at 52-54 ° C.

Analysis:

Calculated for C 18 H 18 NOS: C 45.08; H 8.32; N 10.51 experimentally: C 45.05; H 8.32; N 10.55

Preparation 5 2- (1-Propylthio) acetamide Using the procedure of Preparation 4, but substituting an equimolar amount of 2-propanethiol for 1-propanethiol, 61.2 g (92%) of the title compound were obtained. The white crystals melted at 49.5-51.0 ° C.

Analysis: Calculated for C 18 H 18 NOS: C 45.08; H 8.32; N 10.51 experimentally: C 44.97; H 8.24; N 10.40

Preparation 6 2-Amino-3-benzoyl-5-chloro-α- (methylthio) phenylacetamide To a cold (-70 ° C) solution of 12.77 g (0.055 mol) of 2-amino-5-chlorobenzophenone in 300 ml methylene chloride under nitrogen, 6.0 g (0.0552 mol) of t-butyl hypochlorite in 20 ml of methylene chloride were added. After a further stirring period of 15 minutes, a suspension of 5.8 g (0.055 mol) of α- (methylthio) acetamide in 150 ml of methylene chloride was added. The mixture was stirred at -65 ° C for 1 hour. Triethylamine (5.6 g, 0.055 mol) was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water and the organic layer was dried over magnesium sulfate. The volume of the solution was reduced in vacuo to about 200 ml and the product crystallized as a yellow solid, m.p. 5-174.5 ° C. Yield 6.86 g (37.3%).

Analysis:

Calcd for C 11 H 19 N 2 O 2 Cl 2 SCl: C, 57.40; H 4.52; N 8.37 experimentally: C 57.38; H 4.50; N 8.51 72967 9

Preparation 7 2-Amino-3-benzoyl-α- (methylthio) phenylacetamide To a cold (-70 ° C) solution of 19.7 g (0.10 mol) of 2-aminobenzophenone in 300 ml of methylene chloride under nitrogen was added a solution of 11.5 g (0.10 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride and then, after 10 minutes, a solution of 10.5 g (0.1 mol) of methylthioacetate. amide in 300 ml of tetrahydrofuran. The temperature was maintained at -55 ° C or below during these additions. After another hour at -60 ° C, the mixture was allowed to warm to room temperature and the precipitate was collected by filtration. The precipitate was slurried in 200 ml of methylene chloride and 11 g (0.11 mol) of triethylamine were added. The mixture was stirred for 5 minutes. The solution was washed twice with 100 ml of water and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with diethyl ether and dried to give 13.0 g (43%) of a pale yellow powder, m.p. 153-155 ° C.

Analysis:

Calculated from c 18 H 18 N 2 O 2 S: c 63'98; H 5.37; N 9.33 experimentally: C 63.64; H 5.39; N 9.25

Preparation 8 2-Amino-3- (4-chlorobenzoyl) -α- (phenylthio) phenylacetamide To a cold (-70 ° C) solution of 34.6 g (0.15 mol) of 2-amino-4'-chlorobenzophenone 500 17.3 g (0.15 mol) of 95% t-butyl hypochlorite was added, followed after 10 minutes by a solution of 25.0 g (0.15 mol) of phenylthioacetamide in 400 ml of tetrahydrofuran, which was added. In 20 minutes. The temperature was maintained at -64 ° C or below during these additions. After 2 hours, 20 g (0.2 mol) of triethylamine were added and the mixture was allowed to warm to room temperature. The mixture was concentrated and the residue partitioned between water and methylene chloride. The material insoluble in each phase was collected by filtration, washed with 20% aqueous ethanol and dried to give 36 g (61%) of a pale yellow powder, m.p. 189-191 g.

Analysis:

Calculated for C21H17N2O2SC1: C, 63.55; H 4.32; N 7.06 experimentally: C 63.73; H 4.36; N 7.16 10 '' · '' 72967

Preparation 9 4- [2- (2-Amino-3-benzoylphenyl) -2- (methylthio) acetyl] morpholine

To a cold (-65 ° C) solution of 9.9 g (0.05 mol) of 2-aminobenzophenone and 8.8 g (0.05 mol) of 4- (α-methylthio) acetylmorpholine in 200 ml of methylene chloride , a solution of 5.8 g (0.05 mol) of 95% t-butyl hypochlorite in 20 ml of methylene chloride was added dropwise. After another hour at -60 ° C, 5.1 g (0.05 mol) of triethylamine were added and the mixture was allowed to warm to room temperature. The solution was washed twice with 100 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on 600 g of silica gel, eluting first with diisopropyl ether and finally with 10% diisopropyl ether in acetone. The eluate was concentrated, the residue was dissolved in 150 ml of ethanol and the solution was poured into 400 ml of water. The insoluble solid was collected and crystallized from diethyl ether and dried. The yield was 12.3 g (62%) of yellow crystals, m.p. 119-121 ° C.

Analysis:

Calculated for C 20 H 22 N 3 O 3 S: c 64.84; H 5.99; N 7.56 experimentally: C 65.01; H 5.99; N 7.57

Preparation 10 2-Amino-3-benzyl-5-chloro-g - [(4-chlorophenyl) thio] phenylacetamide

To a cold (-70 ° C) solution of 20 g (0.863 mol) of 2-amino-5-chlorobenzophenone in 500 ml of methylene chloride under nitrogen was added a solution of 9.48 g (0.088 mol) of t-butyl hypochlorite. in ml of methylene chloride. After stirring for a further 15 minutes, a solution of 17.35 g (0.0863 mol) of α- (4-chlorophenylthio) acetamide in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene chloride was added. The mixture was stirred at -70 ° C for 2 hours, 8.72 g (0.0863 mol) of triethylamine were added and the stirred solution was allowed to warm to room temperature over 2 hours. The reaction mixture was extracted with several portions of water, and the organic layer was dried over magnesium sulfate. The volume of the liquid was reduced to about 500 ml. 500 ml of methylene chloride were added to precipitate the product, which after filtration and drying weighed 16.62 g (44.7%). The yellow solid melted at 198-200 ° C.

Analysis:

Calculated from C 58.48; H 3.74; N 6.49 experimentally: C 58.49; H 3.77; N 6.67

Preparation 11 2-Amino-3-benzoyl-5-chloro-α- (phenylthio) phenylacetamide To a cold (-70 ° C) solution of 80.72 g (0.349 mol) of 2-amino-5-chlorobenzophenone in 1.5 liters methylene chloride under nitrogen, 39.1 g (0.360 mol) of t-butyl hypochlorite in 100 ml of methylene chloride were added. After stirring for 10 minutes, a solution of 59.1 g (0.354 mol) of α- (phenylthio) acetamide in 1.5 liters of tetrahydrofuran was added. The mixture was stirred for 1.25 hours at -65 ° C, 37.5 g (0.371 mol) of triethylamine were added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water, and the organic layer was dried over anhydrous sodium sulfate. The volume of the solution was reduced in vacuo and a yellow solid precipitated which on recrystallization from acetonitrile was a yellow solid, m.p. 190-191 ° C (decomposes).

Analysis:

Calculated from the formula: C 63.55: C, 63.55; H 4.32; N 7.06 experimentally: C 63.62; H 4.29; N 7.08

Preparation 12 2-Amino-3-benzoyl-α- (phenylthio) phenylacetamide Following the procedure of Preparation 11, but substituting an equimolar amount of 2-amino-5-chlorobenzophenone for 2-amino-benzophenone, the title compound was obtained in 57% yield. After recrystallization from methylene chloride-diethyl ether-hexane, the compound melted at 153-154 ° C.

Analysis:

Calculated for C 21 H 19 N 2 O 2 S: C, 69.59; H 5.01; N 7.73 Experimentally: C 69.33; H 5.00; N 7.76

Preparation 13 2-Amino-3-benzoyl-g- (methylthio) -N-methylphenylacetamide A solution of 29.6 g (0.15 mol) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70 ° C and 17.9 g of 12,72967 (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml of methylene chloride were added. To the mixture (-70 ° C) was added dropwise a solution of 17.2 g (0.15 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride. The temperature was maintained at -65 ° C or below for 1.5 hours, after which 15.1 g (0.15 mol) of triethylamine were added rapidly. The solution was allowed to warm to room temperature and washed with water. The organic solution was concentrated and the residue crystallized upon stirring with isopropyl ether. The solid was recrystallized from isopropyl alcohol to give 31 g (65%) of yellow needles, m.p. 149.0 to 150.0 ° C.

Analysis:

Calculated from the formula c17H; [8N2O2S: C, 64.94; H 5.77; N 8.91 experimentally: C 65.24; H 5.83; N 8.99

Preparation 14 2-Amino-3-benzoyl-α- (methylthio) -N, N-dimethylphenylacetamide A solution of 29.6 g (0.15 mol) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70 ° C: en and 20.0 g (0.15 mol) of 2-methylthio-N, N-dimethylacetamide were added. To the mixture (-70 ° C) was added dropwise a solution of 17.2 g (0.15 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride. The temperature was maintained at -65 ° C or below for 1.5 hours, after which 15.1 g (0.15 mol) of triethylamine were added rapidly. The solution was allowed to warm to room temperature and washed with water. The organic solution was concentrated and the residue crystallized on stirring with isopropyl ether. The solid was recrystallized from isopropyl alcohol to give 39.8 g (81%) of bright yellow crystals, m.p. 153-155 ° C.

Analysis:

Calculated for c 18 H 20 N 2 O 2 S: C, 65.83; H 6.14; N 8.53 experimentally: C 65.87; H 6.15; N 8.52

Preparation 15 2-Amino-3- (4-fluorobenzoyl) -α- (n-propylthio) phenylacetamide A solution of 21.5 g (0.1 mol) of 4'-fluoro-2-aminobenzophenone in 400 ml of methylene chloride , cooled to -70 ° C and 11.5 g (0.1 mol) of 95% t-butyl hypochlorite was added over 15 minutes keeping the temperature below -66 ° C. To this solution of 13,72967 was added a solution of 13.3 g of 2-n-propylthioacetamide in 50 ml of methylene chloride over 10 minutes.

o

The solution was stirred for 1 hour at -65 to -70 ° C and then allowed to warm to 0 ° C, whereupon 10.2 g (0.1 mol) of triethylamine were added. The solution was stirred for 10 minutes and then washed with water. The organic solution was dried over magnesium sulfate. After concentrating the mixture under reduced pressure, the residue was crystallized from isopropyl alcohol and dried to give 19.5 g (56%) of yellow crystals, melting at 140-142 ° C.

Analysis:

Calculated from C H N O SF: C 62.41; H 5.53; N 8.09 18 19 2 2 Experimental: C 62.34; H 5.58; N 8.04

Preparation 16 2-Amino-3-benzoyl-5-chloro-α- (methylthio) -N-methylphenylacetamide

To a solution of 38.3 g (0.166 mol) of 2-amino-5-chlorobenzophenone in 1 liter of methylene chloride cooled to 0-70 ° C under a nitrogen atmosphere was added 18.05 g (0.167 mol) of t-butyl hypochlorite. The solution was stirred for 15 minutes and then a solution of 20.2 g (0.171 mol) of 2-methylthio-N-methylacetamide in 100 ml of methylene chloride was added.

o

The solution was stirred at -70 ° C for 2 hours and 25 ml of triethylamine was added. With stirring, the solution was allowed to warm to room temperature, then extracted with water, and the organic layer was dried over magnesium sulfate. The volume of the solution was reduced to about 400 ml, ether was added and the solution was placed in a refrigerator at about 0 ° C overnight. The crystallized solid was dried under high vacuum for about 4 hours at 50 ° C. The product weighed 31.56 g (54.6%), melting at 170-171 ° C.

14 72967

Analysis:

Calculated from C H N O SCI: C 58.53; H 4.91; N 8.03 17 17 2 2 experimentally: C 58.68; H 4.91; N 8.13

Example 1 2-Amino-3-benzoyl-5-chlorophenylacetamide A mixture of 21.34 g (0.0639 mol) of 2-amino-3-benzoyl-5-chloro-α- (methylthio) phenylacetamide and excess Ra-ney nickel in a mixture of 900 ml of absolute ethanol and 200 ml of dimethylformamide were stirred at room temperature for 45 minutes. The solvent was removed in vacuo to give a yellow solid which, on recrystallization, melted at 213.5-215.0 ° C (decomposes).

Analysis:

Calculated from C H N O Cl: C 62.40; H 4.54; N 9.70 15 13 2 3 experimentally: C 62.35; H 4.58; N 9.74

Example 2 2-Amino-3-benzoylphenylacetamide

To a stirred solution of 9.7 g (0.032 mol) of 2-amino-3-benzoyl-α- (methylthio) -phenylacetamide in 100 ml of tetrahydrofuran was added 80 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). After 10 minutes, the mixture was filtered to remove Raney nickel and the filtrate was concentrated in vacuo. The residue was crystallized from isopropyl alcohol to give 6.0 g (73%) of yellow needles, m.p. 178.5-180.0 C.

72967

Analysis:

Calculated for C 15 H 14 N 2 O 2: 70.85; H 5.55; N 11.02 experimentally: C 70.53; N 5.53; N 11.04

Example 3 2-Amino-3- (4-chlorobenzoyl) phenylacetamide To a stirred solution of 28.5 g (0.077 mol) of 2-amino-3- (4-chlorobenzoyl) -α- (phenylthio) phenylacetamide in 1 liter of tetrahydrofuran was added. 230 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran).

After 15 minutes, the mixture was filtered and the filtrate was concentrated in vacuo to give 17.4 g (84%) of a yellow crystalline solid. Recrystallization from isopropyl alcohol followed by recrystallization twice from absolute ethanol gave yellow needles, m.p. 212-215 ° C.

Analysis:

Calcd for C 15 H 13 N 2 O 2 Cl: C, 62.40; H 4.54; N 9.70 experimentally: C 62.76; H 4.58; N 9.83

Example 4 4- [2- (2-Amino-3-benzoylphenyl) acetyl] morpholine To a stirred solution of 18.5 g (0.05 mol) of 4- [2- (2-amino-3-benzoylphenyl) - 2- (methylthio) acetyl] -morpholine in 300 ml of tetrahydrofuran, 150 g of wet Raney nickel were added. After 15 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. After recrystallization of the residue from isopropyl alcohol, 13.3 g (82%) of bright yellow crystals were obtained, m.p. 156.5 to 158.5 ° C.

Analysis:

Calculated for C 18 H 20 N 2 O 3: C, 70.35; H 6.22; N 8.64 experimentally: C 70.24; H 6.21; N 8.63

Example 5 2-Amino-3-benzoyl-N-methyltenylacetamide A solution of 22.5 g (0.072 mol) of β-amino-3-benzoyl-α- (methylthio) -N-methylphenylacetamide in 400 ml of tetrahydrofuran was treated with 160 g of 11a wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran) for 10 minutes. The mixture was filtered and the filtrate was concentrated. The residue was crystallized from isopropyl alcohol to give 117.2 g (89%) of yellow needles, m.p. 145-146 C.

Analysis:

Calculating from the formula C H NO: C 71.62? H 6.01; N 10.44 16 16 2 2 experimentally: C 71.76; H 6.05; N 10.52

Example 6 2-Amino-3-benzoyl-N, N-dimethylphenylacetamide A solution of 33.0 g (0.1 mol) of 2-amino-3-benzoyl-α- (methylthio) -N, N-dimethylphenylacetamide in 500 ml tetrahydrofuran, treated with 240 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran11a) for 10 minutes. The mixture was filtered and the filtrate was concentrated. The residue was crystallized from isopropyl alcohol to give 27.2 g (96%) of yellow needles, m.p. 123-124 C.

Analysis:

Calculated from C H N O: C, 72.32; H 6.43; N 9.92 17 18 22 experimentally: C 72.34; H 6.42; N 9.98

Example 7 2-Amino-3- (4-fluorobenzoyl) -phenylacetamide A solution of 24.2 g (0.07 mol) of 2-amino-3- (4-fluorobenzoyl) -α- (n-propylthio) phenylacetamide 300 in 1 ml of tetrahydrofuran, was treated with 250 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). The mixture was stirred for one hour and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from 95% ethyl alcohol to give 14.8 g (78%) of yellow needles, melting at 184-186 ° C.

Analysis:

Calculated from C H N O F: C 66.17; H 4.81; N 10.29 Experimentally: C 66.32; H 4.81; N 10.48 17 72967

Example 8 2-Amino-3-benzoyl-5-chloro-N-methylphenylacetamide A solution of 28.33 g (0.081 mol) of 2-amino-3-benzoyl-5-chloro-α- (methylthio) -N-methylacetamide in one liter of tetrahydrofuran, was treated with excess Raney nickel at room temperature for 2 hours. The solution was filtered through celite. The Raney nickel residue was washed with acetone and the washings were filtered. The combined organic filtrates were dried over magnesium sulfate and the volume was reduced to about 300 ml. Excess ether was added and the solution was allowed to stand at room temperature for one hour, followed by refrigeration overnight. The collected and dried yellow solid weighed 20.94 g (85.68%) and melted at 179-180 ° C.

Analysis:

Calculated from C H N O Cl: C 63.48; H 4.99; N 9.25 16 15 2 2 experimentally: C 63.44; H 4.99; N 9.27

Claims (4)

A process for the preparation of pharmaceutically active 2-amino-3-benzoyl-phenylacetamide derivatives of the formula 0. R1 n / ch2-c-N ^ r2 χ_γΎ VV c = o Λ 1. Menetelmä pharmaseuttisesti activist 2-amino-3-bentsoyylifenyyliasetamidijohdannaisten valmistamiseksi, joilla on kaava 1 0. R ·· / ch ~ -cn x L 1 S ^ NH tai halogeni, yes Y on vety tai halogeni, tunnettu siitä, ette pelkistetään yhdiste, jolla on kaava SR30 r1 2 3 II »CH-C-NC ^^ 2 x ~ r T γ ^ Η2 c = o Λ O 2 2 jossa R , R, X yes Y tarkoittavat same kuin noble yes 3 R on phenyyli tai alempi alkyyli. 19 72967 2. The patent tivaatimuksen 1 mucaine menetelmä, tunnettu siitä, one valmistetaan 2-amino-3-bentsoyyli-5-chlorophenylylacetamidia. 3. Patenttivaatimuksen 1 mucaine menetelmä, tunnettu siitä, one valmistetaan 2-amino-3-bentsoyylphenylylacetamidia. 4. Patent tivaatimuksen 1 mucainen menetelmä, tunnettu siitä, one valmistetaan 2-amino-3- (4-chlorobentoyloxy) phenylacetamidia. 5. The patent tivaatimuksen 1 mucaine menetelmä, tunnettu siitä, one valmistetaan 2-amino-3- (4-fluorobentoylyl) phenylacetamide. 4- Y vV where 1 2 R and R are independently hydrogen or lower alkyl, or R and R together with the nearby nitrogen atom form a morpholine group,