RU2425034C1 - Method of producing (e)-4-(6,7-dimethoxy-2-methyl-3-quinolyl)-3-buten-2-one derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing (E)-4-(6,7-dimethoxy-2-methyl-3-quinolyl)-3-buten-2-one derivatives of formula I, where Ia: R¹ and R² - CH₃; Ib: R¹ - CH₃, R² - C₆H₅; Ic: R¹ - CH₃, R² - o-NO₂C₆H₄; Id: R¹ - t-Bu, R² - C₆H₅; Ie: R¹ - t-Bu, R² - p-OCH₃C₆H₄; If: R¹ - p-BrC₆H₄, R² - Ph; Ig: R¹ -CH₃, R² - thiophene; Ih: R¹ - t-Bu, R² - CH₂CH₂Ph; Ii: R¹ - t-Bu, R² - CH₂CH₂Cl; Ij: R¹ - p-BrC₆H₄, characterised by that ortho-aminoacylbenzylfuran derivatives of formula II are boiled in benzene in the presence of phosphorus oxychloride with a reflux condenser for 1.5-3.5 hours depending on substitutes R¹ and R².

EFFECT: obtaining (E)-4-(6,7-dimethoxy-2-methyl-3-quinolyl)-3-buten-2-one derivatives, pitavastatin analogues, and introduction of the required substitute into the desired compound with simultaneous formation of a quinoline nucleus.

2 tbl, 6 ex

Description

The invention relates to the field of organic chemistry - the synthesis of heterocyclic compounds - derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one, which can be used in the synthesis of new drugs pharmaceutical purpose.

The invention relates to the development of a method for producing derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one of the general formula I, which are of interest as substances with potential biological activity, - analogues of pitavastatin [Acemoglu M., Brodbeck A., Helvetica Chimica Acta, 2007, 90, 1069].

Index R ¹ R ² Ia CH ₃ CH ₃ Ib CH ₃ C ₆ H ₅ Ic CH ₃ o-NO ₂ C ₆ H ₄ Ig t-bu C ₆ H ₅ Id t-bu p-OCH ₃ C ₆ H ₄ Ie p-BrC ₆ H ₄ Ph Izh CH ₃

From t-bu CH ₂ CH ₂ Ph Ii t-bu CH ₂ CH ₂ Cl Ik p-BrC ₆ H ₄ CH ₂ CH ₂ NPht

The literature describes various approaches to the synthesis of unsaturated quinoline derivatives, in which the starting compounds already contain the finished quinoline fragment. Thus, quinolyl-3-buten-2-one derivatives can be obtained by aldol condensation of 2-chloroquinolyl-3-carboxaldehyde and acetone in the presence of piperidine and acetic acid [Cziaky Z., Szabo Z., J. Heterocyclic Chem., 1995, 32 , 755]. Also, an aqueous solution of sodium hydroxide can be used as a catalyst in this reaction [Paul S., Gupta M., Synthetic Communications, 2005, 35, 213-222].

Another method for the preparation of quinolyl-3-buten-2-one derivatives is the Horner-Wadsworth-Emmons reaction in the reaction of quinolyl-2-al and β-ketophosphonate in methylene chloride in the presence of lithium chloride and 1,5-diazabicyclo [5.4.0] undec -5-ena (DBU).

The disadvantages of this synthesis method are low product yields, the need for a reaction in a nitrogen atmosphere at a temperature of -10 ° C [Sliskovic D.R., Picard J.A., J. Med. Chem., 1991, 34, 367].

Another modification of this synthesis method is the preparation of quinolyl-3-buten-2-one derivatives by the interaction of quinolyl-2-al and β-ketophosphonate in ethanol and in the presence of K ₂ CO ₃ [Acemoglu M., Brodbeck A., Helvetica ChimicaActa, 2007, 90, 1069].

Quinolyl-3-buten-2-one can also be synthesized from bromquinoline and pent-1-en-3-one under the action of [Pd (C ₃ H ₅ ) Cl] ₂ and 1,2,3,4-tetrakis diphenylphosphinomethylcyclopentane [Lemhadri M., Doucet N., Santelli M., Synlett, 2006, 18, 2935].

The disadvantages of this method are the high cost of the catalyst used, the duration of the reaction (about 20 hours), and the need for synthesis in a nitrogen atmosphere.

The objective of the invention is the development of a method for producing derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one I, which allows to expand the range of potentially biologically active substances and are convenient starting materials compounds for the synthesis of analogues of pitavastatin alkaloid.

The technical result is the provision of the introduction of the desired substituent in the target product while the formation of the quinoline core.

The technical result is achieved by the fact that in the method for producing derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one, orthoaminoacylbenzylfuranes II are boiled in benzene in the presence of phosphorus oxychloride with reverse refrigerator from 1.5 to 3.5 hours, depending on the substituents R ¹ , R ² .

Index R ¹ R ² Ia CH ₃ CH ₃ Ib CH ₃ C ₆ H ₅ Ic CH ₃ o-NO ₂ C ₆ H ₄ Ig t-bu C ₆ H ₅ Id t-bu p-OCH ₃ C ₆ H ₄ Ie p-BrC ₆ H ₄ Ph Izh CH ₃

From t-bu CH ₂ CH ₂ Ph Ii t-bu CH ₂ CH ₂ Cl Ik p-BrC ₆ H ₄ CH ₂ CH ₂ NPht

The basis of the proposed method is the intramolecular reaction of the opening of the furan ring by the action of an electrophilic carbon atom, leading to the formation of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-ones.

Melting points, elemental analysis data, and spectral characteristics of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-ones Ia-k are shown in Table 1.

The obtained technical result allows us to expand the number of derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one Ia-k, and thereby the range of potentially biologically active compounds.

Thus, the set of essential features set forth in the claims, allows to achieve the desired technical result.

Examples of the proposed method for producing (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one

Example 1

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 1, 5 o'clock. Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 33% (0.16 g).

T _pl. = 115 ° C.

Found for C ₂₄ H ₂₅ NO ₃ ,%: C, 76.84; H 6.73; N, 3.72.

Calculated: C, 76.77; H 6.71; N, 3.73.

¹ H NMR spectrum (CDCl ₃ ), (δ, ppm and KCCB, J, Hz): 1.21 (s, 9H, t-Bu), 4.05 (s, 3H, OCH ₃ ), 4.06 (s, 3H , OCH ₃ ), 7.07 (d, J = 15.6 Hz, 1H, = CH), 7.14 (s, 1H, H _Ar ), 7.45-7.53 (m, 3H, H _Ar ), 7.56-7.60 (m, 3H, H _Ar ), 7.83 (d, J = 15.6 Hz, 1H, = CH), 8.35 (s, 1H, H _Py ).

¹³ C NMR Spectrum (CDCl ₃ ), (δ, ppm): 26.4 (3C), 43.2, 56.1, 56.3, 104.8, 108.0, 122.4, 122.5, 125.6, 128.5 (2С), 128.6, 129.6 (2С) , 133.2, 139.5, 140.9, 145.4, 150.2,153.6, 157.6,203.7.

Example 2

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 7.5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 1, 5 o'clock. Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 88% (0.42 g).

Example 3

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 3 hours . Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 45% (0.22 g).

Example 4

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 7.5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 3 hours . Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 82% (0.39 g).

Example 5

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 4, 5 o'clock. Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 69% (0.33 g).

Example 6

A mixture of 0.5 g (1.4 mmol) of 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa, 7.5 ml of phosphorus oxychloride and 25 ml of benzene is refluxed for 4, 5 o'clock. Then the reaction mixture was poured into 800 ml of water and neutralized with a solution of sodium hydroxide (50 g) in 200 ml of water, extracted with methylene chloride (3 × 150 ml). The combined organic fractions were dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue is separated on silica gel of the KSK brand (manufactured by Sorbpolymer LLC) fraction 5-40 microns, eluent is methylene chloride. Recrystallized from methylene chloride / petroleum ether mixture. Yield 64% (0.31 g).

Table 2 shows the effect of the reaction time and the concentration of phosphorus oxychloride on the yield of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one (examples 1-6) .

As can be seen from table 2, the optimal condition for the synthesis of the target product (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one I is boiling 2- [5- (t -butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene IIa in the presence of phosphorus oxychloride for 1.5 hours at a ratio of compound Ia: phosphorus oxychloride = 1 mol: 7.5 ml. A longer reaction time is accompanied by a strong gumming and, as a result, a decrease in the yield of the target product. Carrying out the reaction at a higher concentration of phosphorus oxychloride also leads to the resinification of the reaction mixture.

table 2 Effect of reaction conditions on the yield of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one IIa Example Ratio Reaction time, hour Exit, % compound Ia, mol POCl ₃ ml one one 5 1,5 33 four one 7.5 88 2 one 5 3 45 5 one 7.5 82 3 one 5 4,5 69 6 one 7.5 64

Boiling the starting 2- [5- (tert-butyl) -2-furylmethyl] -4,5-dimethoxy-1-phenylcarboxamidobenzene in the presence of 5 ml of phosphorus oxychloride for 1.5 hours does not allow complete conversion of the starting compounds and yield (E ) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one is 33%. When boiling benzylfuran under these conditions for 4.5 hours leads to its complete conversion, but the yield of the target product does not exceed 69%.

The inventive method obtained a number of derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one Ia-k.

Claims (1)

The method of obtaining derivatives of (E) -4- (6,7-dimethoxy-2-methyl-3-quinolyl) -3-buten-2-one of the general formula I

characterized in that derivatives of orthoaminoacylbenzylfuranes II are boiled in benzene in the presence of phosphorus oxychloride under reflux for 1.5-3.5 hours, depending on the substituents R ¹ and R ² .