HU224441B1 - N,n-substituted amino-methylen-imidazolinone derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to N, N-substituted aminomethyleneimidazolinone derivatives of formula VI. In formula (VI), R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, naphthyl or phenyl optionally substituted with halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy - hydroxy, 3,4-methylenedioxy or (C1-C4 alkyl) substituted with 2-amino, R5 and R6azone or different and are C1-6 alkyl, phenyl C1-C6 alkyl - or C 6-10 aryl. The above compounds are important intermediates in the preparation of 2-substituted 5-chlorimidazole-4-carbaldehyde. The 2-substituted 5-chloro-imidazole-4-carbaldehyde compounds of formula (I) are important intermediates in the preparation of blood pressure lowering drugs or herbicides.

Description

(57) Extracts

The present invention relates to Ν, Ν-substituted aminomethyleneimidazolinone derivatives of formula (VI). In the general formula (VI)

R is hydrogen, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 3 -C 6) -cycloalkyl, naphthyl or phenyl optionally substituted with halogen, nitro, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, substituted with hydroxy, 3,4-methylenedioxy or (C ₁ -C ₄ alkyl) ₂ -amino,

R ₅ and R ₆ may be the same or different and represent

C 1-6 -alkyl, phenyl-C 1 -C 8 -alkyl or

C 6 -C 10 aryl.

The above compounds are important intermediates in the preparation of 2-substituted 5-chloroimidazole-4-carbaldehydes.

The 2-substituted 5-chloroimidazole-4-carbaldehyde derivatives of formula (I) are important intermediates in the preparation of antihypertensive drugs or herbicides.

HU 224 441 Β1

The scope of the description is 6 pages (including 1 page figure)

HU 224 441 Β1

The present invention relates to novel N, N-substituted aminomethyleneimidazolinone derivatives of formula (VI). In the general formula (VI)

R is hydrogen, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 3 -C 6) -cycloalkyl, naphthyl or phenyl optionally substituted with halogen, nitro, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, substituted with hydroxy, 3,4-methylenedioxy or (C 1 -C ₄ alkyl) ₂ -amino,

R ₅ and R ₆ may be the same or different and are C 1 -C 6 alkyl, phenyl-C 1 -C 8 alkyl or C 6 -C 10 aryl.

The above compounds are important intermediates in the preparation of 2-substituted 5-chloroimidazole-4-carbaldehydes.

The 2-substituted 5-chloro-imidazole-4-carbaldehyde derivatives of formula (I) are important intermediates for the preparation of antihypertensive drugs (U.S. Patent No. 4,355,040) or herbicides (U.S. Patent No. 2,804,435). .

Several methods are known for preparing these compounds.

In U.S. Patent No. 4,355,040, I reacted 2-amino-3,3-dichloroacrylonitrile with aldehyde to give the corresponding azomethine derivative, of which 2-substituted 5-halo-imidazole-4- carbaldehyde is obtained. The patent specification does not contain experimental data. The disadvantage of the synthesis is that the 2-amino-3,3-dichloroacrylonitrile starting material must be prepared from dichloroacetonitrile in the reaction with blue acid / sodium cyanide. The highly toxic reaction components and the precautionary measures that they require as early as the starting material make the whole process unsuitable for the industry.

U.S. Pat. No. 4,355,040 also discloses a further three-step variant wherein the first step is cyclization of the amidine hydrochloride to dihydroxyacetone under high pressure of NH ₃ , halogenation of the imidazole alcohol and subsequent oxidation to the aldehyde.

It has been shown that ring sealing requires an NH ₃ pressure of more than 20 bar. The oxidation of alcohol operates in the presence of chromium oxide. Obviously, oxidation catalyzed by heavy metals, which are generally not recyclable, can no longer be authorized from today's ecological point of view.

The preparation of the compounds of the formula I according to the Hungarian patent application P 94 03 263 is carried out by the first step of the preparation of a glycine ester hydrohalide of the formula II - in the formula II - R ₁ is an alkyl group, and X is halogen, with an imidate ester of formula (III), wherein R is as defined above, and R _{2 is} alkyl, in the presence of a base to give the 2-substituted imidazolin-4-one of formula (IV) - in formula (IV), R is as defined above - in a second step, with a Ν, Ν-substituted formamide acetal of formula (V)

wherein R ₃ and R _{4 are the} same or different and are alkyl or aralkyl, while R ₅ and R ₆ may be the same or different and are as defined above, and reacting the resulting aminomethyleneimidazolinone of formula VI - where R, _R5 and R are as defined above - with phosphorus oxychloride or phosgene in chlorinated.

In the formulas (I) to (VI), the groups R ₁ , R _1t R ₂ , R ₃ , R ₄ , R ₅ and R 9 are as follows: alkyl groups are straight or branched, (C ₄ -C ₆ ) alkyl groups, preferably methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, pentyl and its isomers or hexyl and its isomers. In the meaning of R, the n-butyl group is preferred. Preferably, the radicals R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R 9 are (C ₁ -C ₄ ) alkyl. Alkenyl is a straight or branched (C ₂ -C ₆ ) -alkenyl group such as propen-1-yl, propen-2-yl, buten-1-yl, buten-2-yl, butene-3- il, pentenyl and isomers or hexenyl and isomers. Preferred alkenyl groups are butene-2- and -3-yl.

Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

By aralkyl is meant phenyl-C 1 -C 6 -alkyl, preferably benzyl.

Aryl is preferably phenyl.

Halogen is understood to mean chlorine, bromine or iodine, preferably chlorine.

The present invention relates to novel Ν, Ν-substituted aminomethyleneimidazolinone derivatives of formula (VI) which are useful as starting materials in the final step of the above synthesis. The compounds of formula (VI) may exist in the (E) or (Z) isomeric form. An especially favorable representative of the (Z) -2-butyl-4-dimethylamino-methylene-2-imidazoline, that is to say compound (VI) wherein R = n-butyl, R ₅ and R = methyl.

In the reaction sequence (II) + (III) -> (IV) + (V) - »(VI) + CI -> (l), only the part (IV) + (V) -> (VI) Considering that the full pathway is the subject of Hungarian Patent Application Publication No. P 94 03 263; the description of this application is considered to be known.

The novel Ν, Ν-substituted aminomethyleneimidazolidone derivatives of formula (VI) are prepared according to the invention by reacting a 2-substituted 3,5-dihydroimidazol-4-one derivative of formula (IV) - where R is as defined above

- and a Ν, sz-substituted formamide acetal of formula (V) - wherein R ₃ and R _{4 have the} same or different meanings and are alkyl or aralkyl, while R ₅ and R ₆ may be the same or different and have the same meanings as defined above - we respond.

Examples of Ν, Ν-substituted formamide acetals of formula (V) include: Ν, Ν-dimethylformamide dialkyl acetals, preferably Ν, Ν-dimethylformamide dimethyl acetal (R ₃ , R _4). R _s and R ₆ is methyl).

The reaction is carried out using an inert solvent such as an aliphatic alcohol, a halogenated hydrocarbon or an aromatic compound.

EN 224 441 Β1 let; suitable solvents include methanol, ethanol, dichloromethane or toluene. The reaction can be carried out without solvent, in which case acetal is the solvent.

The reaction is preferably carried out at a temperature of -50 ° C to 100 ° C, but most preferably at room temperature.

The (VI) contacting N, N-substituted aminomethylene imidazolinones - where R, _R5 and _R6 are as defined above - are unknown in the art; and as important intermediates of important syntheses are the subject of the invention. For example, compounds of formula VI may be chlorinated to compounds of formula I (see embodiments).

The 2-substituted 3,5-dihydroimidazol-4-one of formula (IV) required as a starting material for the preparation of the Ν, Ν-substituted aminomethyleneimidazolidine derivatives of formula (VI) is a glycine ester of formula (II). by reaction of a hydrohalide with an imide ester of formula (III) in the presence of a base (see embodiments). The compound of formula (IV) does not necessarily have to be isolated, but can be further reacted in a so-called single process to form the final product of formula (VI).

The invention will now be further illustrated by the following examples.

Example 1 Preparation of (Z) -2-Butyl-4-dimethylaminomethylene-2-imidazolin-5-one (VI) from 2-butyl-2-imidazol-5-one (IV)

To a solution of 2.80 g (20 mmol) of 2-butyl-2-imidazolin-5-one in 20 ml of methanol was added 2.85 g (about 92%, 22 mmol) of Ν, Ν-dimethylformamide dimethylacetal while the temperature rises from 18 ° C to 26 ° C. After 45 minutes, the solution was evaporated and the product dried under high vacuum. 3.88 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one are obtained (> 90% by 1 H-NMR), which is about 2-butyl-2-imidazol-5-one. 90% yield. The product was recrystallized from ethyl acetate, m.p. 114-116.5 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) 0.95 (3H, t);

1.42 (2 H, m);

1.68 (2 H, m);

2.53 (2 H, t);

3.17 (3H, bs);

3.55 (3H, bs);

7.03 (1H, s);

10.35 (1H, bs).

Example 2 Preparation of (Z) -2-Butyl-4-dimethylaminomethylene-2-imidazolin-2-one (VI) from pentanoic acid methyl ester (III) (No single-process process (IV))

To a solution of sodium hydroxide (1.59 g, 39.42 mmol) in methanol (13 mL) at 0 ° C was added glycine methyl ester hydrochloride (5.00 g, 39.42 mmol) in one portion while maintaining the temperature at -10 ° C. Decreased to C. The mixture was stirred for 15 minutes while the temperature again rose to 0 ° C. After adding 4.73 g (39.42 mmol) of methyl pentanoic acid, the mixture was stirred at room temperature for 3 hours. 5.00 g (43.39 mmol) of N, N-dimethylformamide dimethylacetal are then added over 5 minutes and the mixture is stirred for a further 3 hours. The solvent was removed in a rotary evaporator and a mixture of dichloromethane (40 mL) and water (15 mL) was added to the residue. After separation of the phases, the organic phase is washed with 10 ml of water, the combined aqueous phases are washed with dichloromethane (2 x 20 ml), the combined organic phases are dried over magnesium sulphate, evaporated and the residue is dried under high vacuum.

6.70 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one are obtained (about 90% by 1 H NMR), yielding about 78% of pentanoic acid methyl ester. equivalent to.

Example 3

Preparation of 2-Butyl-5-chloro-imidazole-4-carbaldehyde (I) from (Z) -2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one (VI) (Use of new compounds) 1 A mixture of 00 g (5.12 mmol) of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one and 3.20 g (20.48 mmol) of phosphorus oxychloride was heated at 100 ° C for 45 minutes. We keep C. The phosphorus oxychloride (1.76 g) was evaporated on a rotary evaporator and ethyl acetate (6 ml) was added to the residue. The resulting mixture was poured into water (20 mL) and stirred at room temperature for 5 minutes. The pH was adjusted from 0.34 to 7 with aqueous 30% w / w sodium hydroxide. The mixture was extracted with ethyl acetate (2 x 10 mL), the organic layers were dried over magnesium sulfate, filtered, evaporated and the residue dried under high vacuum.

0.89 g of 2-butyl-5-chloro-imidazole-4-carbaldehyde (purity> 95% by 1 H NMR) were obtained, 93% based on 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one. yield.

¹ H-NMR (CDCl 3): δ = 12.44 (bs, 1H), 9.65 (s, 1H),

2.87 (t, J = 7.5 Hz, 2H), 1.79 (m, 2H), 1.39 (m, 2H),

0.93 (t, J = 7.5 Hz, m 3H).

¹³ C-NMR (CDCl 3): δ = 177.7 (d), 155.3 (s), 142.0 (s),

126.0 (s), 29.9 (t), 28.5 (t), 22.3 (t), 13.6 (q).

IR (KBr): v = 1673, 1515 cm ^-1

C ₈ Hi ₁ CIN ₂ O, Calculated: 186.0560, Found:

186.0563.

Example 4 Preparation of (Z) -2-Butyl-4-dimethylaminomethylene-2-imidazolyl-5-one (VI) from 2-butyl-2-imidazolin-5-one 5.00 g (35.67 mmol) 2-butyl-2-imidazolin-5-one and

A solution of 7.02 g (39.24 mmol) of N, N-dimethylformamide diisopropylacetal in 25 ml of dichloromethane was stirred at room temperature for 2.5 hours. The solvent was removed in a vacuum evaporator and the residue was dissolved in dichloromethane (40 mL). The resulting solution was washed with water (2 x 10 mL), dried over magnesium sulfate, evaporated in a rotary evaporator and the residue dried under high vacuum. 5.37 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one (> 90% H-NMR) are obtained.

EN 224,441-1), corresponding to a yield of 71% relative to 2-butyl-2-imidazolidin-5-one.

Example 5 Preparation of (Z) -2-Butyl-4-dimethylaminomethylene-2-imidazolin-5-one (VI) from pentanoic acid methyl ester (III): 1.59 g (39.42 mmol) of sodium To a solution of the hydroxide in 13 ml of methanol at 0 ° C was added 5.00 g (39.42 mmol) of glycine methyl ester hydrochloride in one portion while the temperature dropped to -10 ° C. The mixture was stirred for 15 minutes while the temperature again rose to 0 ° C. After adding 4.73 g (39.42 mmol) of methyl pentanoic acid, the mixture was stirred at room temperature for 3 hours. N, N-dibutylformamide dimethylacetal (9.00 g, 43.39 mmol) was then added over 5 minutes and the mixture was stirred for an additional 3 hours. The solvent was removed in a rotary evaporator and a mixture of dichloromethane (40 mL) and water (10 mL) was added to the residue. After separation of the phases, the organic phase is washed with water (10 ml), the combined aqueous phases are washed with dichloromethane (2 x 20 ml), the combined organic phases are dried over magnesium sulfate, evaporated and the residue is dried under high vacuum.

6.92 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one are obtained (about 80% by 1 H NMR), yielding about 72% of pentanoic acid methyl ester. equivalent to.

Claims (2)

PATENT CLAIMS N, N-substituted aminomethyleneimidazolinone derivatives of formula (VI) wherein: R is hydrogen, (C 1 -C 6) -alkyl, (C 2 -C 6) -alkenyl, (C 3 -C 6) -cycloalkyl, naphthyl or phenyl optionally substituted with halogen, nitro, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, substituted with hydroxy, 3,4-methylenedioxy or (C ₁ -C ₄ alkyl) ₂ -amino, R ₅ and R ₆ may be the same or different and are C 1-6 alkyl, phenyl-C ₁ -C ₆ alkyl or C 6-10 aryl. The (Z) -2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one of claim 1. HU 224 441 Β1 Int Cl ⁷ : C 07 D 233/96 O-R, / H C-O R. \ N-R. \