PL203902B1 - Method for the manufacture of derivatives of 3-(dilakiloamino)-1-(heteroaryl)-prop-2-en-1-one - Google Patents

Abstract

A process for the preparation of 3-(dialkylamino)-1-(heteroaryl)-prop-2-en-1-one derivatives represented by the general formula 1, wherein R1 is an unsubstituted or substituted five- or six-membered heterocyclic ring selected from the group consisting of pyridines, thiophenes and furans; and R2 is C1-C3 alkyl, the aryl acyl compound is reacted with N,N-dialkylformamide dialkyl acetal to remove the C1-C3 alkanol formed during the reaction. 3-(dialkylamino)-1-(heteroaryl)-prop-2-en-1-one derivatives are valuable starting compounds in the synthesis of biologically active substances.

Description

Description of the invention

The present invention relates to a process for the preparation of 3- (dialkylamino) -1- (heteroaryl) -prop-2-en-1-one derivatives represented by the general formula 1, in which R1 is pyridinyl and R2 is C1-C3 alkyl.

3- (dialkylamino) -1- (heteroaryl) -prop-2-en-1-one derivatives can be valuable starting compounds for the synthesis of biologically active compounds, for example substituted pyrazolo [1,5-a] pyrimidines with anxiolytic properties described in in US Patent Nos. 4,281,000 and 4,374,988 or the group of pyridinylpyrimidines as tyrosine kinase inhibitors described in EP Patent 0 564 409.

According to the disclosure of US patents US 4,281,000 (equivalent to EP 0 025 819) and US 4 374 988 and EP 0 233 461, the derivatives of 3- (dialkylamino) -1-heteroaryl-prop-2-en-1-one are obtained by refluxing a mixture of an aryl acyl compound of formula 2, wherein R 1 is an unsubstituted or substituted five or six membered heterocyclic ring selected from the group consisting of pyridines, thiophenes and furans, with a molar excess (1.09-4.7 eq.) of N dimethyl acetal , N-dimethylformamide, a compound of Formula 3 wherein R2 and R3 are methyl groups, for 6-16 hours.

The product is usually isolated by cooling the reaction mixture and filtering the formed crystals, or by concentrating the reaction mixture under reduced pressure, treating the residue with hexane and filtering the formed crystals.

The crude product thus obtained typically requires purification by direct crystallization from a suitable solvent or filtration of a solution of the crude product in methylene chloride through magnesium silicate followed by crystallization.

Alternatively, the purified product is isolated by concentrating the reaction mixture under reduced pressure, dissolving the residue in methylene chloride and filtering the resulting solution through magnesium silicate followed by crystallization.

These compounds are usually well soluble in organic solvents and water, resulting in a low yield of crystallization product (50-66%) compared to that of crude solidified product (85-89%).

The basic synthesis and product yield parameters disclosed in the above-mentioned patents are summarized in Table 1 below.

T a b e l a 1

No next Substrate DMF dimethyl acetal [eq] Response time [h] Performance the product 1 2 3 4 5 ₁ a) 2-acetylpyridine 1.688 6 89.2% (d) ₁ b) 2-acetylpyridine 1.276 16 . . . (e) 2 ^b ) 3-acetylthiophene 1.357 12 86.5% (d) 66.6% (g) ₂ c) 3-acetylthiophene 1.582 16 . . . (d, g) 3 ^a) 2-acetyl-5-methylthiophene 4.704 16 85.5% (e) 4 ^c) 2-acetylthiophene 1.582 16 63.7% (d, g) 5 ^a) 2-acetyl-5-methylfuran 3.763 16.5 52.6% (f) 6 ^b) 3-acetylpyridine 1.094 16 50.2% (d, g) 6 ^c) 3-acetylpyridine greater than 1.0 16 . . . (d, g) 7 ^b) 3-propionylpyridine 1.119 15 48.9% (h) 8 ^b) 3-acetylfuran 0.994 16 . . . (d) ₈ c) 3-acetylfuran 2,000 16 . . . (d, g)

PL 203 902 B1 cont. table 1

1 2 3 4 5 9 ^b) 2-acetyl-6-methylpyridine 1.424 16 . . . (e) 10 ^b) 4-acetylpyridine 1.276 16 . . . (d) 11 ^c) 2-acetylfuran 1.657 16 . . . (d, g)

^a) according to EP 0 233 461 ^b) according to US 4,281,000 ^c) according to US 4,374,988

The method of extracting the product:

(d) concentrating the reaction mixture under reduced pressure, treating the residue with hexane and filtering the formed crystals;

(e) cooling the reaction mixture and filtering the formed crystals;

(f) concentrating the reaction mixture under reduced pressure, dissolving the residue in methylene chloride, and filtering the resulting solution through a layer of magnesium silicate, followed by crystallization from methylene chloride-hexane;

(g) recrystallization from methylene chloride-hexane;

(h) concentration of the reaction mixture under reduced pressure, cooling and filtering of the crystals, dissolving the crystals in methylene chloride and filtering the obtained solution through a layer of magnesium silicate, followed by crystallization from the methylene chloride-hexane mixture

According to the table above, by reacting 3-acetylpyridine according to US Patent 4,281,000 (example 1) with 1.09 equivalents of N, N-dimethylformamide dimethyl acetal, crystallization of the crude product gives 3- (dimethylamino) -1- (3- pyridyl) -prop-2-en-1-one with a yield of only 50%.

Another reason for the low yield may be the incomplete conversion of the aryl acyl compound to the desired product.

We have now found that the degree of conversion of the aryl acyl compound to the desired product can be increased without increasing the molar excess of the N, N-dialkylformamide dialkyl acetal used, removing from the reaction medium the alkanol formed in the process, which lowers the reaction temperature.

The invention therefore resides in a process for the preparation of 3- (dialkylamino) -1- (heteroaryl) -prop-2-en-1-one derivatives represented by the general formula 1, in which R1 is pyridyl and R2 is C1-C3 alkyl, characterized by that the arylacyl compound of Formula 2, wherein R 1 is pyridyl, is reacted with a N, N-dialkylformamide dialkyl acetal of Formula 3 wherein R 2 and R 3 are independently C 1 -C 3 alkyl groups, removing the C 1 -C 3 formed during the reaction alkanol.

In a preferred embodiment of the invention, the aryl acyl compound of formula 2 is 3-acetylpyridine, which is reacted with dimethylformamide methyl acetal to give 3- (dimethylamino) -1- (3-pyridyl) prop-2-en-1-one, intermediate in the synthesis of imatinib.

According to the process of the invention, the reaction of the arylacyl compound with the N, N-dialkylformamide dialkyl acetal is carried out with a slight excess of acetal, for example 1.2-2.0, preferably 1.5 equivalents of the acetal per equivalent of the aryl acyl compound.

A suitable reaction medium is the acetal used in the reaction, although it can also be carried out in an inert organic solvent with a boiling point not lower than that of the acetal used.

The reaction is carried out at the reflux temperature of the reaction mixture until the disappearance of the acyl compound (TLC), the reaction times when using N, N-dimethylformamide dimethyl acetal, which is also the reaction solvent, generally lower than those of the prior art.

The formed C1-C3 alkanol can be removed from the reaction medium in any way, for example by distillation, periodically or continuously or periodically (at specified intervals during the reaction or once after its completion), using an apparatus with a distillation head. Vigreux.

The product is isolated from the reaction medium in the usual manner by concentrating the reaction mixture by distilling off excess acetal and possibly additional organic solvent, and then filtering off the precipitate formed.

PL 203 902 B1

This product can be further purified by crystallization from a suitable solvent or used in the next synthesis steps without further purification.

The method according to the invention enables a significant reduction in the synthesis time and increase in the yield of the product obtained. Thus, by reacting 3-acetylpyridine according to example 1 of US patent 4,281,000 with 1.5 equivalents of N, N-dimethylformamide dimethyl acetal and changing the solvents used for crystallization, 3- (dimethylamino) -1- is obtained after crystallization (3-pyridyl) prop-2-en-1-one in a yield of about 62%.

However, in the case of an identical reaction, carried out with the removal of the methanol formed, the product can be obtained after crystallization with a yield of about 72%.

The following examples illustrate the invention.

P r z k ł a d 1

A mixture of 3-acetylpyridine (181.5 g; 1.498 M; 1 eq.) And DMF methyl acetal (299 ml; 268.20 g; 2.250 M; 1.5 eq.) Was heated under reflux for 7.5 h. . The reaction mixture was concentrated under reduced pressure. The residue was dissolved hot in toluene (200 ml), cooled to about 50 ° C and hexane (340 ml) was added while stirring. The mixture was cooled to room temperature and the resulting precipitate was filtered off. The resulting precipitate was washed with a toluene-hexane mixture (100 ml: 100 ml) and then with a toluene-hexane mixture (100 ml: 150 ml). After drying, 162.4 g (61.5%) of 3- (dimethylamino) -1- (3-pyridyl) prop-2-en-1-one were obtained, m.p. 81-83 ° C;

¹ H NMR (CDCl3, 200 MHz): 2.91 (3H, s, CH3), 3.14 (3H, s, CH3), 5.66 (1H, d, J = 12.4 Hz, 3H ), 7.35 (1H, dd, J = 8.1 and 4.7 Hz, 5'-H), 7.85 (1H, d, J = 12.4 Hz, 2-H), 8.19 (1H, dt, J = 8.1, 1.9 and 1.9 Hz, 4'-H), 8.67 (1H, dd, J = 4.7 and 1.9 Hz, 6'-H) , 9.09 (1H, d, J = 1.9Hz, 2 '-H).

P r z k ł a d 2

A mixture of 3-acetylpyridine (24 g; 0.198 M; 1 eq) and DMF methyl acetal (40 ml; 35.88 g; 0.301 M; 1.52 eq.) Was heated under reflux for 1 h. Then from the reaction mixture for 1 hour. methanol was distilled off using a Vigreux cap. Cyclohexane (25 mL) was added to the warm, stirred residue and the mixture was cooled to room temperature. The resulting precipitate was filtered off and washed with cyclohexane (30 ml). After drying, 23.0 g (65.8%) of orange 3- (dimethylamino) -1- (3-pyridyl) prop-2-en-1-one was obtained.

P r z k ł a d 3

A mixture of 3-acetylpyridine (1272 g; 10.50 M; 1 eq.) And DMF methyl acetal (1877 g; 15.75 M; 1.5 eq.) Was refluxed for 1 h. Then from the reaction mixture for 1 hour. methanol was distilled off using a Vigreux cap. The mixture was refluxed again for 6 hours, then for 1 hour. methanol was distilled off. The reaction mixture was concentrated under reduced pressure. The residue was dissolved while hot in toluene (1400 ml), cooled to about 50 ° C and hexane (2400 ml) was added while stirring. The mixture was cooled to about 10 ° C and the resulting precipitate was filtered off. The resulting precipitate was first triturated in a toluene-hexane mixture (700 ml: 700 ml) and filtered, then triturated in a toluene-hexane mixture (700 ml: 1050 ml), filtered and washed with lexane (500 ml). After drying, 1322 g (71.4%) of orange 3- (dimethylamino) -1- (3-pyridyl) prop-2-en-1-one was obtained.

Claims (9)

1. A method for the preparation of 3- (dialkylamino) -1- (heteroaryl) -prop-2-en-1-one derivatives represented by the general formula 1, wherein R1 is pyridyl and R2 is C1-C3 alkyl, by condensing an aryl acyl compound with acetal, characterized in that the aryl acyl compound of formula 2 in which R1 is pyridyl is reacted with a dialkyl acetal of N, N-dialkylformamide of formula 3 in which R2 and R3 independently represent C1-C3 alkyl groups, removing the resulting C1-C3 alkanol reaction. 2. The method according to p. The process of claim 1, wherein the 3-acetylpyridine is reacted with dimethylformamide methyl acetal to give 3- (dimethylamino) -1- (3-pyridyl) prop-2-en-1-one. 3. The method according to p. The process of claim 1, wherein the C1-C3 alkanol is periodically or continuously removed. 4. The method according to p. The process of claim 2, wherein the C1-C3 alkanol is periodically removed. 5. The method according to p. The process of claim 1, wherein the reaction is carried out with an excess of acetal. PL 203 902 B1 6. The method according to p. The process of claim 1 or 5, wherein the reaction is carried out in an excess of 1.2-2.0 equivalents of acetal per 1 equivalent of arylacyl compound. 7. The method according to p. 6. The process of claim 6, wherein the reaction is carried out in an excess of 1.5 equivalents of acetal to 1 equivalent of aryl acyl compound. 8. The method according to p. A process as claimed in claim 1, characterized in that N, N-dimethylformamide dialkyl acetal is used in the condensation reaction with an arylacyl derivative. 9. The method according to p. The process of claim 8, characterized in that N, N-dimethylformamide dimethyl acetal is used in the condensation reaction with an arylacyl derivative.