FI60197C - NOW FOERFARANDE FOER FRAMSTAELLNING AV BENSAMIDER - Google Patents

Description

TTÄE ^ Tl Γηΐ ANNOUNCEMENT

iJ (1) utlAggnincsskrift 60197 • jypS C (45) Patent «ly -.- sr: * Uy 13 12 ΙΤύΙ

Patent meJdelnt ^ (51) K ».lk? /Lnt.CI.3 C 07 C 103/82 FINLAND —FINLAND (21) P» wuttlh «kunwM-IWtw« eknlng 222h / 7h (22) Hakumliptlvl - Amekningadug 22.07 · 7 ^ * '(23) AlkupUvi — GlMghutsdag 22.07 · 7 ^ (41) Tullut Julkkukal - Bllvlt effuntlig 25 * 01.75

Patent and Registration Office .... .... ...........

_. '. . . , (44) Nihtlvikflpsnon a kuul. | UliuU * ufl pvm. - 0_

Patant- eeh registerstyrelsan v 'Antttkm utiagd och uti ^ kriftan pubimnd 31.0Θ. 8l (32) (33) (31) Requested atuolkau * —Begird prlorltet 2U.07 · 73

France-France (FR) 83391/73 (71) Societe d'Etudes Scientifiques et Industrielles de 1'Ile-de-France, U6, Boulevard de Latour-Maubourg, 75 Paris 7 ° »France-France (FR) (72) Yoshinari Sato, Tokyo, Japan-Japan (jP) (7 ^) Oy Kolster Ab (5U) New method Bent s amide en ready st anti sex - Now you want to be framed with gasoline

The invention relates to a new process for the preparation of benzamide derivatives having interesting pharmacological properties, in particular as digestion modifiers. Of these derivatives, metoclopramide, i.e. N- (2-diethylaminoethyl) -2-methoxy-U-amino-5-chlorobenzamide, is a known compound.

It has now been found that these compounds can be obtained in maximum yields thanks to the new process which is the subject of the invention.

The invention relates to a new process for the preparation of benzamides of the formula CONH-R 1 11 (IV) r 2 wherein R 1 is alkyl or alkenyl, R 1 is hydrogen, amino, nitro or acetamido, R 1 is dialkylaminoalkyl and X 1 is hydrogen, halogen or alkylsulfonyl.

2 601 97

The invention is characterized in that an o-hydroxybenzoic acid derivative of the formula

COOH

^. OR.

R2 wherein R 1, R 8 and X are as defined above, or a salt thereof is reacted with an amine of formula

HgN-Rjj (III) wherein is as defined above, in the presence of triphenylphosphine and di (2-pyridyl) disulfide or o, o'-dinitrophenyl disulfide.

The substituted benzoic acids of formula I used as starting materials are described in FR patents 1 kj 0 025 and 1 kj6 925.

In the starting material (i), R 1 represents an alkyl group which may be, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc., or an alkenyl group which may be, for example, allyl.

The tertiary aminoalkyl group R 1 comprises, for example, the groups 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-dipropylaminoethyl, 2- (or 3-) dimethylaminopropyl, 2- (or 3-) diethylaminopropyl, 2- {or 3- or U- ) diethylamino-butyl. As the salts of the compound (lii), for example, salts of mineral acids, for example, hydrochloride, sulfate, etc., and salts of organic acids, for example, acetate, maleate, tartrate, etc. can be mentioned.

In the case that X represents an alkylsulfonyl radical, the alkyl is methyl, ethyl, propyl, butyl.

The salts of the starting compound (I) are preferably metal salts, such as copper salts, mercury salts, lead salts, manganese salts, chromium salts.

In the reaction according to the invention (I) + (lii) - (IV), a sulfenamide of the formula r3-s-nh-ru is formed as an intermediate, in which R1 is an organic radical.

3 60197

The reaction of the invention can be carried out in the presence of a compound capable of replacing the sulfur of the intermediate thio compound to give benzamide (IV) in the highest yields.

Such a compound is particularly preferably used when the organic disulfide is di (2-pyridyl) disulfide.

Such a compound need not be used in the case where the starting compound (I) is used as a heavy metal salt.

Examples of compounds capable of replacing the sulfur of the thio compound include mineral acid salts of heavy metals, e.g., mercuric chloride, zinc chloride, copper chloride, lead sulfate, manganese sulfate, etc., -nitrophenol, 2, k-dinitrophenol, N-hydroxysuccinimide, p-methoxyphenol, etc., an acid according to Pearson's theory, e.g. a sulphenoic acid ester, e.g. a methyl or ethyl or tert-butyl ester of o-nitrophenylsulphenic acid, 2, U-dinitrophenylsulfonic acid methyl or tert-butyl ester, etc., olefinic compound, e.g. 2,3-dihydropyran, n-butyl vinyl ether.

The reaction is generally carried out in a solvent, for example, dimethylformamide, pyridine, ether, dioxane, methylene chloride, tetrahydrofuran, benzene, toluene, etc., i.e., in any solvent inert to the reaction.

The reaction may be carried out in the presence of an acid, for example pivalic acid, N-hydroxysuccinimide, phenol, p-nitrophenol, picric acid, or a base, for example triethylamine, N-alkylmorpholine, etc. or water.

The reaction temperature is not limited, and the reaction can be carried out at room temperature.

The benzamide (IV) can be converted into a salt of a mineral acid, for example, hydrochloride, hydrobromide, phosphate, sulfate, etc., or a salt of an organic acid, such as acetate, propionate, maleate, tartrate, citrate, salicylate, etc.

4,60197

The following examples illustrate the invention.

Example 1 N- (2-Diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide 6 ml of a solution of 1 g of 2-methoxy-4-amino-5-chlorobenzoic acid in dimethylformamide was added to a solution of 5 g of ml of purified dimethylformamide, 0.6 g of 2- (diethylamino) ethylamine, 1.4 g of triphenylphosphine and 1.2 g of di- (2-pyridyl) disulfide.

After the mixture was stirred at room temperature for 1 hour, dimethylformamide was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. The aqueous layer was basified by the addition of 1 Ν 'solution of sodium hydroxide. The solution was saturated with sodium chloride and then extracted twice with ethyl acetate. The organic base was washed with an anhydrous saturated solution of sodium chloride, followed by distillation of ethyl acetate.

The obtained N- (2-diethylamino) -ethyl-2-methoxy-4-amino-5-chlorobenzamide was recrystallized from benzene to give colorless crystals with a melting point of 145-146 ° C. This melting point infrared spectrum and thin layer chromatography indicated that the compound was the same as the control.

The following compounds were prepared in the same manner as in Example 1: N- (2-diethylamino) ethyl-2-methoxy-4-acetamido-5-chlorobenzamide, m.p. 99-510 ° C.

} 7- (2-diethylamino) -ethyl-2-methoxy-4-nitro-5-chlorobenzamide, m.p. 70-72 ° C.

Using N- (2-diethylamino) ethyl-2-methoxy-4-acetamido-5-chlorobenzamide as a starting material, N- (2-diethylamino) ethyl-2-methoxy-4-amino 5-Chlorobenzamide (melting point 145-146 ° C) by hydrolysis with hot aqueous sodium hydroxide solution.

Reduction (with Raney nickel in alcohol) of N- (2-diethylamino) ethyl-2-methoxy-4-nitro-5-chlorobenzamide gives the same metoclopramide (m.p. 145-146 ° C).

Example 2 N- (2-Diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide

To a 250 mL flask equipped with a stirrer and thermometer were added 6.2 g of Ο, Ο'-dinitrophenyl disulfide, 25 mL of dimethylformamide, and 2.3 g of Ν, Ν-diethylenediamine. After stirring for 30 minutes at ambient temperature, the reaction mixture was poured into a solution of 5.2 g of triphenylphosphine and 4.9 g of 2-methoxy-4-acetamido-5-chlorobenzoic acid in 30 ml of dimethylformamide.

5,60197

After stirring for 1 hour, the solvent was evaporated in vacuo, the residue was dissolved in 50 ml of ethyl acetate and the organic solution was extracted with 50 ml of dilute hydrogen chloride solution.

The aqueous solution was filtered, then 50 ml of sodium hydroxide solution was added and refluxed for 1 hour, cooled, the crystals were filtered, washed with water, and dried in an oven at 50 ° C.

5.5 g of crude product (55 »1 $) * melting point 142-144 ° C were obtained.

The infrared spectrum was the same as that of the control sample, but showed some impurities in the product.

Example 5 N- (2-Diethylamino) -ethyl-2-methoxy-4-amino-5-chloro-benzamide

The procedure was the same as in Example 2, except that: 4 g of 2-methoxy-4-amino-5-chlorobenzoic acid was used as the acid, - heating in the presence of sodium hydroxide was not necessary, - the product was recrystallized from benzene to give the same product as above. Melting point 144 ° C, yield recrystallized, 0.2 g ($ 3.3).

Example 4 N- (2-Diethylamino) -ethyl-2-methoxy-5-methylsulfonylbenzamide

The procedure was the same as in Example 3, and 4.6 g of 2-methoxy-5-methylsulfonylbenzoic acid was used as a starting material to give 3.8 g of crude product (57-9 °) * melting point 112 ° C.

The infrared spectrum was similar to that of the control sample, but showed the presence of impurities to a small extent.

Example 5 N- (2-Diethylamino) -ethyl-2-methoxy-4-aminobenzamide

The same procedure as in Example 2 was applied, and 4.2 g of 2-methoxy-4-acetamidobenzoic acid was used as a starting material.

The acetylated compound was extracted with methylene chloride from an aqueous suspension of sodium hydroxide, and the residue was evaporated. The organic phase was deacetylated by refluxing for 8 hours in a solution of 50 ml of propanol and 5 ml of 40% sodium hydroxide solution.

The propanol was evaporated in vacuo, then N- (2-diethylamino) ethyl-2-methoxy-4-aminobenzamide was extracted with methylene chloride, and the organic solution was evaporated to dryness under reduced pressure to give 1.6 g of crude product ($ 30.2) as a brown solid. as an oil.

The nuclear magnetic resonance spectrum corresponded to the desired structure, but showed the presence of impurities to a small extent.

6 60197

Example 6 N- (2-Diethylamino) ethyl-2-methoxy-4-amino-5-bromobenzamide

The procedure of Example 2 was applied, but 5.8 g of 2-methoxy-4-acetamido-5-bromobenzoic acid was used as the acid to give 3.5 g ($ 50.9) of crude product, m.p. 147 ° C.

The infrared spectrum was similar to that of the control sample, but showed the presence of small amounts of impurities.

Example 7 N- (2-Diethylamino) ethyl-2-allyloxy-4-amino-5-chlorobenzamide

The procedure of Example 2 was applied, but 5.4 g of 2-allyloxy-4-acetamido-5-chlorobenzoic acid was used as the acid. The obtained crystals were saponified with sodium hydroxide and redissolved in dilute hydrochloric acid. The solution was filtered and then re-basified with sodium hydroxide to give 3.35 g (51.5 / 0 of crude product, m.p. 128 ° C).

The nuclear magnetic resonance spectrum corresponded to the desired structure, but showed the presence of impurities to a small extent.

Example 8 N- (2- (Diethylamino) ethyl] -2-allyloxy-4-amino-5-chlorobenzamide

The procedure of Example 7 was applied, but 4.4 g of 2,2'-dithiodipyridine was used as disulfide to give 2.2 g (35-6%) of crude product, m.p. 128 ° C.

The nuclear magnetic resonance spectrum was similar to Example 7 ·

Example 9 N- (2-Diethylamino) -ethyl-2-methoxy-5-methylsulfonylbenzamide

The procedure of Example 4 was applied, but 4.4 g of 2,2'-dithiodipyridine was used as the disulfide to give 3.1 g (48.4 °) of crude product, m.p. 117 ° C.

The infrared spectrum was similar to that of the control sample.

Claims (1)

τ 60197 Claim: A new process for the preparation of benzamides of the formula CONH-R 2 OR. XX X r 2 wherein R 1 is alkyl or alkenyl, is hydrogen, amino, nitro or acetamido, is dialkylaminoalkyl and X is hydrogen, halogen or alkylsulphonyl, characterized in that the o-hydroxybenzoic acid derivative of the formula COOH AT 'I * 2 wherein Rp R 9 and X are cloudy as above, or a salt thereof is reacted with an amine of formula HgN-R 2 (III) wherein R 1 is as defined above, triphenylphosphine and di (2-pyridyl) disulfide or o, o '- in the presence of dinitrophenyl disulphide ·