NZ211831A - The preparation of 3-cyano-4-aminoacetophenones and their use as intermediates in preparing 2-amino-5-(1-hydroxy-2-(alkyl- or dialkyl-amino)ethyl) benzonitriles - Google Patents

Abstract

1. Process for preparing 3-cyano-4-amino-acetophenones of general formula see diagramm : EP0158932,P4,F1 wherein R represents a hydrogen or fluorine atom, characterized in that a 3-cyano-4-acetamino-acetophenone of general formula see diagramm : EP0158932,P4,F2 wherein R is defined as hereinbefore, is saponified with potassium hydroxide, sodium hydroxide, potassium or sodium methoxide in the presence of methanol as solvent at temperatures up to the boiling point of the reaction mixture and the compound of general formula I is isolated from the reaction mixture.

Description

New Zealand Paient Spedficaiion for Paient Number £11 831 \t I \ 17 APR 1985 ' i * Patents form No.5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "CHEMICAL PROCESS" -I-»WE DR. KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG a Body Corporate organised under the laws of the Federal Republic of Germany, of D-7950 Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which -I-/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 2 1*831 2 IIP 147-122 Chemical Process The invention relates to a process for the preparation of 3-cyano-4-arainoacetophenones of general formula I R 0 \l (I) h2n c - ch3.

CN (wherein R represents a hydrogen or fluorine atom).

These compounds are important intermediate products in the preparation of valuable pharmaceutical compositions and feed additives; as feed additives/ the compounds of general formula V described hereinafter bring about more intensive use of animal feed, and may be utilised in animal husbandry for the promotion of more rapid growth and of an increase in the ratio of lean meat to fat.

In view of the worldwide shortage of high-grade protein there is considerable interest in such active substances. In order to provide sufficient quantities of these active substances the discovery of a simple method of production which is environmentally favourable is urgently needed.

The 3-cyano-4-aminoacetophenones of general formula I occupy an important key position in the production of the active substances. It was therefore important to find a simple method of preparing them which ensures not only a high yield but also a high quality product.

Thus, according to the invention there is 211831 provided a process for the preparation of compounds of general formula I as hereinbefore defined, which comprises saponifying a compound of general formula II (ii) ; 5 (wherein R is as hereinbefore defined) by means of an alkali metal hydroxide (such as, for example, ' potassium hydroxide or sodium hydroxide) or an ■ri alkali metal methoxide (such as, for example, potassium .J ' methoxide or sodium methoxide) , and in the presence of methanol. j In a preferred embodiment, potassium hydroxide \> / is placed in methanol and the mixture is heated i ; to a temperature of between 30 and 50°C, and then, j , preferably gradually, the compound of general formula ^ 15 II is added thereto. The saponification is completed j by heating the reaction mixture to a temperature j of between 40°C and the reflux temperature, preferably \ to the reflux temperature, and maintaining the reaction mixture at this temperature until the 20 saponification reaction is completed. If the reaction mixture is then evaporated to dryness, the residue taken up in water and the solution mixed with an inorganic acid (preferably concentrated hydrochloric y ^ » acid) the compound of general formula I is obtair^d ! 'V J 25 as a crystalline precipitate. The precipitate ;• - "t ii 17 FEB1988 j is washed once more and dried. The corresponding / ' A compound of general formula I occurs in pure form.'v<v /• ... £ !M * Generally, for the compound wherein R represents ' a hydrogen atom, yields of between 80 and 90% of theory may be achieved, based on the compound of general formula II used; if R represents a fluorine atom the yields are 2 1183 1 somewhat lower.

The saponification of the compounds of general formula II to form compounds of general formula I under the conditions specified above was not foreseeable. The deacylation of compounds of general formula II cannot be carried out either in acidic or in alkaline aqueous media in the desired manner when using conventional methods of saponification. As is also known from the literature [cf. A. Graham, Synthetic Communications 10 [3], 241-243 (1980)J, a compound possessing a reactive cyano group adjacent to an acylamino group undergoes, in the presence of a strong acid, a cyclisation reaction according to the reaction plan which follows: or with dilute acids the corresponding 2-acylaminobenzamide is obtained. It has also been observed that in aqueous alkaline medium the cyano group is also saponified to form the amide group. This method i3 used for the preparative recovery of condensed pyrimidines.

By using the process according to the invention it has been possible for the first time to carry out the deacylation of the acetyl group whilst maintaining the integrity of the cyano group; this deacylation is possible only if alkali metal hydroxides in methanol or alkali metal methoxides in methanol are used.

The starting compounds of general formula II may be obtained, for example, by reacting a compound of general formula IV 211831 o ii ch3 - c - (IV) (wherein R is as hereinbefore defined) with copper(I) cyanide.

The reaction is conveniently carried out in the presence of a solvent such as, for example, pyridine or dimethylformamide at temperatures of between 100 and 150°C, and the product is purified with, for example, ethyl acetate (cf. also Houben-Weyl, Volume 8: Oxygen Carpounds III, page 303 (available on request)).

The starting compounds of general formula IV may be obtained, for example, from the corresponding 4-acetamidoacetophenone (for the preparation thereof see Beilstein E II, 14, 33) by bromination using bromine in the presence of glacial acetic acid/water [cf. L.C. Raiford, H.L. Davis, J. Am. Chem. Soc. 50, 158 (1928) and Beilstein E II, 3_4, 33 (available on request)].

The compounds of general formula I are important intermediate products for the preparation of compounds of general formula V R H2n ch - ch2 - n oh x"l (V) cn (wherein R is as hereinbefore defined, R^ represents a hydrogen atom or a C1-4 alkyl group and Rj represents 211831 a C}_4 alkyl group) which may be used, for example, as feed additives, and which bring about greater growth in fat-stock and poultry and also lead to increased utilisation of feed; they also increase 5 the ratio of lean meat to fat (cf. New Zealand Patents 194308 and 196249). However, these compounds also have therapeutically useful properties, for example an effect on the B-receptors, particularly a Sj" mimetic activity. A particularly interesting compound 10 of general formula V is that compound wherein R and R^ each represents a hydrogen atom and R2 represents an isopropyl group (melting point 165-167°C).

The compounds of general formula V may readily be prepared from the corresponding 3-cyano-4-aminoaceto-15 phenone by the following steps: a) bromination, in conventional solvents such as, for example, glacial acetic acid or tetrahydrofuran, using elemental bromine or copper (II) bromide; b) reaction, at temperatures of up to 20°C, of the resulting05-bromo-3-cyano-4-aminoacetophenone with an amine of general formula HNR^R2 (wherein R^ and R2 are as hereinbefore defined) to form the corresponding aminoketone; and c) reduction of the aminoketone, to form the amino-25 alcohol of general formula V, with the aid of sodium borohydride in water. i o 3 1 The following non-limiting Examples are intended to illustrate the invention more fully: A. Examples of the preparation of the end products Example 1 3-Cyano-4-aminoacetophenone .2 g (0.45 mol) of potassium hydroxide and 300 ml of methanol are placed in a reaction vessel and the contents of the vessel are heated \ 10 to 40°C. Within 2 to 4 minutes 30 g (0.15 mol) of 3-cyano-4-acetamidoacetophenone is added and the reaction mixture is heated under reflux for 20 minutes. It is then concentrated by evaporation to dryness and the residue is mixed with 300 ml 15 of water; 40 ml of concentrated hydrochloric acid is added and the crystalline 3-cyano-4-aminoacetophenone formed is precipitated. The mixture is cooled i to 10°C and stirred for a further hour. After * suction filtration, washing of the filter residue with water and drying of the residue at 60°C, 21 g of beige 3-cyano-4-aminoacetophenone is obtained, corresponding to a yield of 87.5% of theory. Melting point: 161.5°C.

If sodium hydroxide and methanol are used 25 in the same molar ratios and under the same reaction conditions, 3-cyano-4-aminoacetophenone is obtained in a yield of 80% of theory.

Example 2 30 3-Cyano-4-ami noacetophenone ^ 3.8 kg (59.6 mol) of potassium hydroxide ^ and 45.6 litres of methanol are placed in a reaction vessel and the contents of the vessel are heated to 40°C. Within 5 to 10 minutes 4.58 kg (22.6 mol) 35 of 3-cyano-4-acetamidoacetophenone is added; the mixture is refluxed for 25 minutes, the solvent ~c* J "3 2 118 is eliminated and 60 litres of water, followed by 6 litres of concentrated hydrochloric acid, are added to the dry residue. The work-up is continued as described in Example 1.

Yield: 3.0 kg of 3-cyano-4-aminoacetophenone corresponding to 82.8% of theory.

Melting point: 161.5°C.

Using potassium methoxide, a yield of 76% of theory is obtained.

Example 3 3-Cyano-4-amino-5-fluoroacetophenone Using the same method as in Example 1, 3-cyano-4-acetaraido-5-fluoroacetophenone is saponified 15 with potassium hydroxide, at 45 to 50°C with a reaction time of 24 hours, to form 3-cyano-4-amino-5-fluoroacetophenone.

Yield: 55% of theory; using sodium hydroxide 48% of theory.

B. Example of the preparation of the starting compound 3-cyano-4-acetamidoacetophenone Example 4 In accordance with Rosenmund-V.Braun's reaction 25 (as described in Houben-Weyl, Volume 8: Oxygen Compounds III, page 303), 70 g (0.273 mol) of 3-bromo-4-acetamidoacetophenone [prepared using the method of L.C. Raiford and H.L. Davis, J. Am.

Chem. Soc. 50, 158 (1928)) and 24.5 g (0.273 mol) 30 of copper(I) cyanide are heated in 150 ml of dimethyl-formamide in an oil bath to 130°C for 2.5 hours.

Copper(I) bromide is precipitated, which is suction filtered at the end of the reaction, using a suction filter at 95°C, and washed with 20 ml of dimethylformamide. 35 The warm filtrate is poured into 300 ml of water, whereupon the 3-cyano-4-acetamidoacetophenone and

Claims (10)

I •3 *w" 2 t 183 1 - 9 - the remaining copper(I) bromide are precipitated. The resulting suspension is stirred for a further 2 hours, then suction filtered, and the filter residue is washed with water. The crude product 5 is dried at 60°C and is then decocted, first with 700 ml of ethyl acetate and again with 300 ml of ethyl acetate, in order to eliminate the copper salt; the combined extracts are evaporated down to a total volume of 200 ml. In order to complete ] 10 the precipitation, a further 200 ml of petroleum ether (b.p. 60-70°C) is added to the warm ethyl acetate suspension. After cooling and suction filtration, the filter residue is dried at 60°C until a constant weight is obtained, j 15 yield: 36 g of 3-cyano-4-acetamidoacetophenone ! corresponding to 65.2% of theory, based on the j amount of 3-bromo-4-acetamidoacetophenone used. Melting point: 170°C. i G 211831 ) u - 10 - WhfAT^WE CLAIM I*. ■Cla imjt

1. A process for the preparation of compounds of general formula I r J 0 h2h - 12w - ch3. (i) cn (wherein R represents a hydrogen or fluorine atom) which comprises saponifying a compound of general formula II (ii) 10 (wherein R is as defined above) by means of an alkali metal hydroxide or an alkali metal methoxide^ in the presence of methanol.

2. A process as claimed in claim 1 wherein the alkali metal hydroxide comprises potassium hydroxide 15 or sodium hydroxide. A* 6 /

3. A process as claimed in claim 1 wherein the |z ^ p£B1983' ' alkali metal methoxide comprises potassium methoxide^ or sodium methoxide.

4. A process as claimed in claim 1 wherein the 20 compound of general formula II is gradually added over a period of a few minuteo; to a potassium hydroxide-methanol mixture which has been pre-warmed to a temperature of between 30 and 50°C. ' E I yj .'<*» -11- 21183.1

5. A process as claimed in any one of the preceding claims wherein the reaction mixture is heated to a temperature of between 40°C and the reflux temperature and maintained at such a temperature until the 5 saponification reaction is completed.

6. A process as claimed in claim 5 wherein the said temperature is the reflux temperature of the reaction mixture.

^ 7. A process for the preparation of compounds ^ 10 of general formula I as described in claim 1 substantially as herein described.

8. A process for the preparation of compounds of general formula I as described in claim 1 substantially as herein described in any one of Examples 15 1 to 3.

9. Compounds of general formula I as described in claim 1 whenever prepared by a process as claimed in any one of the preceding claims.

10. Use of the compounds of general formula I 20 as described in claim 1 when prepared by a process as claimed in any one of claims 1 to 8 as intermediates in the preparation of compounds of formula V % t' J k OH CN CH - CH2 - (V) E f/ S O s 'fry *17 FEB/983,f 25 - . r- ^ e iv" ■ (wherein R is as defined in claim 1, represents a hydrogen atom or a C^_^ alkyl group and Rj represents a C1-4 alkyl group). DR KARL THOMAE GmbH By their Attorneys BALDWIN SON & CAREY C. QoucJLa^&f-y