Process for the preparation of derived from benzophenone.

AS AFRICAN AND MALAGASY

P. 887

Yaounde (Cameroon) Patent International Patent Classification: c07 № 00964

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8 To 40 hr 26 December 1964 requested Mn to the O.A.M.P. I-.

(G.P. no. 51,059) by the Company anonymous F Hoffman-to-rock and a CIE, resident of Switzerland.

Issued 7 August 1968, published at Official ballot no. 2 of 1968. Priority: Patent application filed in the United States of America under the trade name no. 282,886 24 May 1963 Aaron L Nelson and Hugh-Israel and Rachlin.

The present invention relates to a method for

preparation of benzophenone derivatives of the formula

general:

in which R has the meaning mentioned, as well as

alkylation products are compounds of the formula

iI which.

The term "lower alkyl", as it will be used

subsequently, designates groups hydrocarbons

straight and branched, such as methyl,

ethyl, propyl, isopropyl, and so forth by "halogen", is

four halogens are heard, either chlorine, the fluorinated, the

bromine and iodine.

The method of the invention is characterized in that

reacting P-nitro aniline with a halogénnre of

halogenobenzoyl or benzoyl chloride in the presence of

zinc, and, if necessary, is converted in the pro -

cut a reaction in the descrip - benzodiazepine derivative

churning and that alkyl optionally DC last.

The method of the invention provides a

2-amino 5-nitrate benzophenone by acylation of P-nitro aniline with a benzoyl halide, even though it is known that such reactions are not applicable to the nitro benzene ring.

Reacting a benzoyl halide (chloride is preferred) with P-nitro aniline in the presence of zinc chloride is advantageously implemented at an elevated temperature, preferably above about 130 °c, because the reaction mixture tend to solidify at a low temperature. The reaction should be carried out in an anhydrous medium and can be implemented in the absence of solvents, except of course the reaction partner even. The reaction yet can be performed in the presence of an inert solvent. Advantageously used equimolar amounts of the reaction partners, but they can also react in any proportion, because the concentration is not critical for the success of the reaction.

The transformation of 2-amino 5-nitrate benzophenones in benzodiazepine derivatives can for example be carried out by reaction with a derivative of glycyl or of halogéno-acetyl. The compounds of the general formula II, thereby causing, may optionally be alkylated with an alkylating agent lower.

Example 1. 3,495 kg - 2,087 kg of benzoyl chloride and anhydrous zinc chloride are placed into an tricol of 22 liters, equipped with stirrer, thermometer, a reflux condenser and a purifier. While stirring, the reaction mixture is heated to 140 °c, and the temperature is maintained at 140" C. inside the balloon. By small portions, 1,657 kg is added P-nitro-aniline is in the space of 30 min. Once the addition is complete, the temperature is raised to 200 - 205 °c, and then allows the reaction mixture for 1 hour at this temperature. Then added a mixture of 1,740 liter water and 36% hydrochloric acid to 2,785 kg. Once the addition has been completed, is placed a second reflux condenser on the balloon and stirred the reaction mixture for 15 hours at reflux still. Then, cooled to 100 - 105 °c and added a mixture of 613 ml ammonium hydroxide to 26 % and 4.2 liters of water. The reaction mixture is then extracted with 6.5 liters of toluene (to about 50 - 60 °c) and the aqueous phase is separated; then, extracted once again with 2 liters of fresh toluene (50 - 60 °c to about). The extracts are washed with separate toluic 6 liters of hydrochloric acid (to about 50 - 60 °c) 3n, this in three equal portions. Then added 2 liters of hot water (to about 50 - 60 °c) to the extract toluic and the resulting mixture stirred vigorously. Then added slowly sodium hydroxide to 50 % until a pH of 11. The aqueous alkaline phase is separated and washed toluic extract 2 times with one liter of hot water (about 50 - 60 °c). The extract is dried toluic azéotropiquement (steam bath) with concentration under reduced pressure to a volume of about 1 liter. Then allowed the reaction mixture to cool to room temperature, after which the reaction product begins to separate as lustrous brown crystals. These are separated by filtration, washed with small portions of toluene (5 - 10 °C) cold and dried in vacuum to 100 °c. The 2-amino 5-nitrate benzophenone resulting melts at 158 - 159" 0.

A confectioneries a solution of 7.26 g of 2-amino 5 a-nitrobenzophéuone in 850 ml of benzene, added 2.8 ml of bromoacetyl bromide. Passing dry air through the solution until all the hydrogen bromide has been eliminated. The solution henzenic is subsequently washed with water until neutral reaction, and then dried using sodium sulfate is concentrated in vacuum. The residue is crystallized from a mixture of benzene and petroleum ether, steam is produced from the 2 a-bromoacètamido-to-5-nitrate henzophénone as colorless needles melting at 155 - 156 °c.

A solution of 2 g of the product obtained in 30 ml of dioxane is treated with 10 ml of a methanolic solution of ammonia to 13 %. The solution is allowed to stand for 16 hours at ambient temperature, then concentrated in vacuum at a temperature of 25 °c the water bath. The residue is distributed between 50 ml of ether and 50 ml of hydrochloric acid 0, 3n. The solutiou ethereal is extracted again with 50 ml of hydrochloric acid 0, 3n. The combined acid extracts are filtered and rendered alkaline. using ammonium hydroxide. The ohtenu reaction product is separated by filtration and dried in vacuum.

This gives the 2 a-aminoacétamido-to-5-nitrate benzophenone melts at 156 - 158 °c (dec.). By recrystallization in a mixture of chloroform and ether, is ohtient yellowish needles melting at 166 - 167 °c (dec.).

The aqueous solution is neutralized with hydrochloric acid and gives, after rest, fawn brown crystals of 7-nitrate 5-phenyl-3h L, 4 a-henzodiazépin-a 2 - (1 Η) οη℮.

Heating is applied 2 to-aminoacétamido-to-5-nitrate benzophéuone during 5 minutes at 165 - 187 °c. The compound bottom, foam and resolidifies. The mass is dissolved in chloroform and discolored with activated carbon. The solution chloroformée, is concentrated in vacuo and treated with ether, then the ohtient 7-nitrate 5-phenyl-3h L, 4 a-benzodiazepin-to-2 (LHRH) one derivatives crystallized.

B. a solution of 2.42 g of 2-amino 5-nitrate benzophenone and 4.2 g of ethyl glycinate hydrochloride in 75 ml de pyridine are heated 16 hours at reflux. The pyridine is removed in a vacuum and the residue distrihué between 166 ml of benzene and 100 ml of water.

The benzene solution is extracted with 80 ml of sodium hydroxide In and the alkaline extract neutralized with dilute hydrochloric acid. The precipitate is separated by filtration, dried, dissolved in chloroform and filtered for removal of the non-soluble. The solution is concentrated in vacuo chloroformée and the residue crystallized in ether; and the 7 - ohtient is a nitro - 5 - phenyl - 2 - benzodiazepin - 3:00 -1.4 (1 Η) one derivatives crystallized.

5.6 g of the product obtained are suspended in 75 ml of methanol. While stirring, added 1.1 g of sodium methoxide. The yellow-brown color clear solution is concentrated in vacuum to dryness; this gives the yellow sodium derivative. The latter is dissolved in 50 ml of dimethylformamide, then added 3.8 ml methyl iodide dropwise and leaves the temperature up to 30 °c. The reaction mixture is cooled during 1 half hours with agitation. The clear solution is poured into 500 ml brown about stirred ice water. A fine yellow precipitate is separated by filtration, washed with ice water, dewatered to dryness and dried in vacuum to 50 °c using sodium hydroxide. Diluted in ethanol, obtained L-methyl-7-nitrate 5-phenyl-3h L, 4 a-benzodiazepin-to-2 (LHRH)- one derivatives in pure form of needles melting at 156 - 157 °c.

Example 2. - 4,351 kg of ortho-to-clilorobenzoyle chloride and 2,087 kg anhydrous zinc chloride are placed into an tricol of 22 liters equipped with stirrer, thermometer, a reflux condenser and a purifier.

By maintaining the temperature inside the reaction vessel 130 - 140 °c, is added in small portions 1,657 kg of P-nitro-aniline is in 30 minutes to within about. The temperature is then raised to 200 - 205 °c and maintained at this temperature for 1 hour, then added dilute acetic acid (prepared with 2,975 liters of water and 4.25 liters of glacial acetic acid) energisation in within about 45 min. During this time, there can be observed a depression of the temperature. Then added 5,525 liters of concentrated sulfuric acid to the reaction mixture and carrier is heated at reflux. 11 develops a considerable amount of hydrogen chloride and the foam which develops is controlled by addition of a silicone antifoam agent (Dow Rheology Index-to-to Corning Antifoam has). Heating the reaction mixture for 4 hours at reflux and allowed to cool to ambient temperature overnight. The solidified mass is then heated again to 60⁰ G and added by portions 14 liters of hot water (about 60 °c) and 15 liters of hot toluene (about 60 °c.), while the reaction mixture is placed in a funnel to tap, wherein allowed the reaction mixture to a temperature of 60 °c. The aqueous layer is separated and the layer toluic hot washed, in three equal portions, with 6 liters of 3n hydrochloric acid (about 60 °c) hot, then added 6 liters of hot water (at least 60 °c) to the phase toluic. With stirring vigorously, then added to 50% sodium hydroxide solution until a pH of 11. The emulsion ohtenue is filtered through a filtering layer (through hyflo). The phases clear filtrate are then separated and washed with hot toluic layer 8 liters of hot water (at least 60" C.), this into four equal portions. The solution obtained is concentrated to about