JP3533567B2 - A new synthetic method to produce substituted quinolines from substituted anilines - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a compound represented by the above general formula D from a substituted aniline, which has improved regioselectivity and yield, and therefore complicated post-treatment after the reaction. Relates to a method for producing the compound.

[0002]

2. Description of the Related Art A typical known method for synthesizing a substituted quinoline having a substituent on the benzene ring is to obtain quinoline by heating anilines, glycerin and an oxidizing agent in the presence of a strong acid such as sulfuric acid. There is a quinoline synthesis method [RHF Manske, M. Kulka, Org. React. 28, 59-98 (195
3)]. However, since this synthetic method requires a reaction with a strong acid at a high temperature, many by-products other than the target compound are generated, and thus extremely complicated purification is required to obtain the target product. And the yield is not always good. In addition, in the synthetic reaction of substituted quinoline using meta-substituted aniline or 2,3-disubstituted aniline as a raw material, the 5- and 7-position substituted quinolines of the position isomers, 6, and
A mixture of 7- and 5,6-substituted quinolines is produced.
In some cases, one isomer preferentially forms up to 4 times as much as the mixture due to the orientation characteristics of the substituents, but in general, the selectivity of the synthesis reaction is not necessarily high [MHPalmer. , J. Chem. Soc., 3645-3652 (1962)]. Furthermore, the yield was not good.

Further, the compound represented by the general formula D is
A compound that is used as an intermediate in one method in the total synthesis of bindrin, and the efficient reaction of the total synthesis of bindrin is in many steps of the total synthesis.
Improving the intermediate step is also very important in establishing a practical total synthetic reaction, and a production method with improved regioselectivity of a substituted quinoline, especially a substituted quinoline having no substituent on the pyridine ring. The establishment of is highly desired.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a substituted quinoline in which the above disadvantages of the conventional method for producing a substituted quinoline are improved.
In the case of obtaining the target compound represented by the general formula D from a substituted aniline via a cyclization reaction, the present inventors first obtain a sulfonamidated product of the substituted aniline, and add acrolein to the sulfonamidated product. It was found that the regioselectivity and the yield were remarkably improved by using the obtained precursor of the cyclization reaction, and the above problem was solved by using the compound represented by the general formula B in the cyclization reaction. I was able to.

[0005]

The present invention has the general formula A
A substituted aniline sulfonamide compound represented by the formula (wherein R ¹ , R ² and R ³ are independently selected from the group consisting of H, OH, alkoxy group, alkyl, amino, amide and halogen, and R ⁴ is an alkyl group; , Which represents a methyl group or a substituted benzene such as a p-tolyl group) in the alcohol in the presence of acrolein and triethylamine to synthesize an aldehyde intermediate represented by the general formula B, and then the aldehyde intermediate The body is treated with trifluoromethanesulfonic acid [(TfOH: CF ₃ (SO ₂ ) O
H] or under acidic conditions (acidification with hydrochloric acid, sulfuric acid, etc.) to obtain a dihydroquinoline derivative represented by the general formula C, which is treated with MOH (M is Na or K) in DMSO. Is a method for synthesizing the substituted quinoline represented by the general formula D. Preferably, R ¹ is a substituent at the 3-position, R ² is a substituent at the 4-position, each of the substituents is independently selected from H, a hydroxyl group, an alkoxy group, a halogen, and R ³ is H. Is a method for synthesizing the substituted quinoline, more preferably, the cyclization reaction is allowed to proceed in a tetrahydrofuran solution in the presence of hydrochloric acid of 3 N or more. Is the way to do it.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail. A. The compound of the general formula A used in the present invention is prepared by converting a substituted aniline into paratoluenesulfonyl chloride (pTsC).
1) or methanesulfonyl chloride (MsCl) in dichloromethane in the presence of pyridine. Here, instead of using pyridine in dichloromethane, M ₂ CO ₃ (M is Na or K)
It can also be used in a 4-dioxane / water mixed solvent. B. Compounds of general formula A to compounds of general formula B are prepared from acrolein (2 to 10) in an alcohol in which triethylamine (0.1 equivalent to 2 equivalents) is present, eg methanol.
It can be synthesized in a yield of about 100% by adding Michael to (equivalent weight). Here, instead of triethylamine, diisopropylethylamine, diazabicycloundecene,
Tertiary alkylamines such as diazabicyclononene can also be used. C. Substitution of the compound of the general formula B in a dichloromethane solution of trifluoromethanesulfonic acid or in a tetrahydrofuran (THF) solution of hydrochloric acid, sulfuric acid or the like, or 1,4-dioxane solution to give a substituted dihydrogen represented by the general formula C. You can get quinoline. D. The obtained compound of the general formula C is converted to dimethyl sulfoxide (DMSO) in the presence of MOH (M is Na or K).
The compound of the general formula D, which is the target compound of the present invention, can be obtained by treating in the medium (treatment at about 50 ° C. to 140 ° C.).

[0007]

EXAMPLES Specific examples of the substituted quinoline obtained by the synthetic method of the present invention will be described below, but the synthetic method of the present invention is not limited to these. Example 1 Here, a method for synthesizing a compound represented by the general formula D in which R ¹ is substituted with a hydroxy group at the 3-position will be described. A solution of 3-aminophenol (102.6 g, 0.940 mol) in pyridine (470
Under ice cooling, a pyridine solution (500 mL) of p-toluenesulfonyl chloride (denoted as TsCl) (198 g, 0.987 mol) was added dropwise to (mL) over 3 hours. After stirring at that temperature for 30 minutes, the reaction solution was diluted with ethyl acetate and washed with saturated brine. After extracting the aqueous layer with ethyl acetate,
The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue obtained is diluted with ether,
The residue was washed with 1N hydrochloric acid to remove the residual pyridine. The organic layer was further neutralized, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain a starting material Np-tosyl-3-hydroxyaniline (hereinafter referred to as compound 1).

Physical Properties: IR (film, cm ^-1 ): 3260,1600,1493,1304,1149,1091,982,6
90,565,543. ¹ H NMR (400 MHz, DMSO-d ₆ ): d 2.30 (3H, s), 6.39 (1H, d, J = 8.
0Hz), 6.52 (1H, d, J = 7.6Hz), 6.96 (1H, t, J = 7.6Hz), 7.32 (2
H, d, J = 7.6Hz), 7.64 (2H, d, J = 8.8Hz), 9.43 (1H, bs, NH), 1
0.1 (1H, bs, OH). ¹³ C NMR (100MHz, DMSO-d ₆ ): d 21.0,106.9,110.6,116.
2,126.8,129.7,129.9,136.9, 139.2,144.4,157.9. Analysis: Calculated value for C ₁₃ H ₁₃ NO ₃ S: C, 59.30; H, 4.98; N,
5.32. Measurements: C, 59.14; H, 5.05; N, 5.30.

Compound 1 (330 g, 0.940) under argon atmosphere
Mol) and triethylamine (144 ml, 1.034 mol) in methanol solution (MeOH) (3.6 L), acrolein (330 ml, 4.7 mol) was slowly added dropwise under ice cooling.
After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with saturated saline. The aqueous layer was extracted twice with ethyl acetate, the obtained organic layers were combined, and methanol was distilled off under reduced pressure at low temperature as much as possible. The remaining organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 3- (N-3-hydroxyphenyl-Np-tosylpropionaldehyde (hereinafter, referred to as compound 2). The above reaction is represented by the following reaction formula.

[0010]

[Chemical 5]

Physical Properties IR (film, cm ^-1 ) 3430,3029,2736,1720,1595,1483,1455,1
^{. 343,1218,1161,1089,970, 814,755,693,658,577,550 1 H NMR (} 400MHz, CDCl 3): d 2.42 (3H, s), 2.68 (2H, t, J = 7.
2Hz), 3.85 (2H, t, J = 7.2Hz), 6.46 (1H, d, J = 8.0Hz), 6.70 (1
H, s), 6.80 (1H, d, J = 8.0Hz), 7.13 (1H, t, J = 8.0Hz), 9.70 (1
H, s, OH). ¹³ C NMR (100 MHz, CDCl ₃ ): d 21.5,42.8,44.6,50.8,115.
7,116.6,119.8,127.7,129.6,130.0,134.5,139.7,143.9,
156.6,200.4.

3N hydrochloric acid (1.8 L) was added to a tetrahydrofuran (THF) solution (1.8 L) of compound 2 (375 g, 0.940 mol).
Was slowly added and reacted at 60-C for 30 minutes. After the reaction was completed, sodium bicarbonate was added thereto under ice cooling for neutralization. The reaction solution was diluted with ethyl acetate and then washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a 7-hydroxy-1,2-dihydroquinoline derivative (hereinafter, compound 3). The reaction is represented by the following formula.

[0013]

[Chemical 6]

Physical properties: ¹ H NMR (400 MHz, CDCl ₃ ): d 2.35 (3H, s), 4.41 (2H, dd, J = 2.
0,4.0Hz), 5.44 (1H, dt, J = 4.0,9.6Hz), 5.98 (1H, d, J = 9.6H
z), 6.69 (1H, dd, J = 2.0,4.0Hz), 7.08 (2H, d, J = 8.8 Hz), 7.2
5 (1H, s), 7.35 (2H, d, J = 8.0 Hz). ¹³ C NMR (100MHz, CDCl ₃ ): d 21.5,45.3,113.7,113.8,12
0.6,122.7,125.1,127.3,127.7,129.1,136.1,136.2,143.
5,155.4. Analytical, calculated for C ₁₆ H ₁₅ NO ₃ S: C, 63.77; H, 5.02; N, 4.65. Found: C, 61.11; H, 5.32; N, 4.31.

Compound 3 (362 g, 0.940) under argon atmosphere
And a dimethylsulfoxide solution (1.5 L) of potassium hydroxide (248 g, 3.76 mol) were reacted at 130-C for 30 minutes. After returning the reaction solution to room temperature, the reaction solution was acidified with 3N hydrochloric acid under ice cooling. The obtained reaction solution was washed with ethyl acetate three times. Next, the aqueous layer was neutralized with sodium hydrogen carbonate under ice cooling, and then extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 7-
101.5 g (72%, 4 steps) of hydroxyquinoline (Compound 4) was obtained. The reaction formula is represented by the following reaction formula.

[0016]

[Chemical 7]

Physical Properties IR (film, cm ^-1 ) 3423,1610,1503,1336,1293,1162,1089,8
11,690,656,582,562,544. ¹ H NMR (400MHz, DMSO-d ₆ ): d 7.17 (1H, dd, J = 2.0,8.8Hz),
7.25 (1H, dd, J = 5.2,8.8Hz), 7.28 (1H, d, J = 2.8Hz), 7.78 (1
H, d, J = 8.8Hz), 8.16 (1H, d, J = 8.0Hz), 8.73 (1H, dd, J = 2.0,
5.2Hz), 10.2 (1H, s). ¹³ C NMR (100MHz, DMSO-d ₆ ) d 110.0, 118.4, 119.3, 122.3, 1
. 29.3,135.6,149.5,150.5, 158.5 Calcd for _{C 9 H 7 NO:. C} , 74.47; H, 4.86; N, 9.65 Analytical values: C, 74.28; H, 5.08 ; N, 9.49.

Example 2 The experimental result in the following reaction by this invention is shown.

[0019]

[Chemical 8]

Compound 5 was dissolved in dichloromethane, and TfOH (3.8 mL, 0.043 mmol) was added with a syringe at room temperature under an argon atmosphere. The resulting mixture is heated to 50-C under argon.
The mixture was stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The separated aqueous phase was extracted twice with ethyl acetate, and the obtained extract and the organic phase were combined. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography 40
Dihydroquinoline derivative 6 was obtained by developing with ethyl acetate / hexane (78 mg, 80%).

Physical Properties: IR (film, cm ^-1 ): 2930,1490,1346,1336,1158,1065,964,8
^{. 24,760 1 H NMR (400MHz,} CDCl 3): d 2.34 (s, 3H), 2.69 (s, 3H), 4.39
(m, 2H), 6.00-6.03 (m, 1H), 6.57 (d, J = 10.0Hz, 1H), 6.96
(s, 1H), 7.08 (d, J = 8.0Hz, 1H), 7.47 (d, J = 8.0Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): d 20.9,37.5,45.4,124.6,126 .
. 4,127.1,127.4,128.8,129.1,136.8 HR-MS (EI) C 11 H 13 NO 2 Calculated for S:. 223.0667 measured value 223.0664.

Examples 3 to 9

[0023]

[Chemical 9]

Table 1 shows a method for producing a substituted quinoline from the meta-position or 3,4-substituted aniline derivative through the above-mentioned cyclization reaction and the result thereof. Ms = mesyl group, p-Ts =
Paratosyl group, Tf = trifluoromethanesulfonyl group,
THF = tetrahydrofuran

[0025]

[Table 1]

From the isomer production ratio (A: B), the regioselectivity of the reaction is remarkably improved as compared with the above-mentioned conventional synthesis method, and the yield is also remarkably improved. I understand.

[0027]

INDUSTRIAL APPLICABILITY As described above, when the target compound represented by the general formula D is obtained from a substituted aniline via a cyclization reaction, first, a sulfonamidated product of the substituted aniline is obtained. By using the precursor of the cyclization reaction obtained by adding acrolein, the regioselectivity and the yield are enhanced, and the excellent action and effect that the post-treatment after the reaction is simplified are brought about.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 215/58 C07D 215/20 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A substituted aniline sulfonamide compound represented by the general formula A (wherein R ¹ , R ² and R ³ are H,
Independently selected from the group consisting of OH, alkoxy group, alkyl, amino, amido, halogen, and
On the other hand, it is a group arranged at the meta or / and para position. R ⁴
Represents an alkyl group or substituted and unsubstituted benzene. ) Is reacted with acrolein in an alcohol in the presence of triethylamine to synthesize an aldehyde intermediate represented by the general formula B, and then the aldehyde intermediate is cyclized in trifluoromethanesulfonic acid (TfOH) or under acidic conditions. To obtain a dihydroquinoline derivative represented by the general formula C, which is dissolved in DMSO with MOH (M is Na
Alternatively, a method of synthesizing the substituted quinoline represented by the general formula D by treating with K). [Chemical 1] [Chemical 2] [Chemical 3] [Chemical 4] 2. R ¹ is a substituent at the 3-position, R ² is a substituent at the 4-position, each of said substituents being independently selected from H, a hydroxyl group, an alkoxy group, a halogen, R ³
Is H, The method for synthesizing a substituted quinoline according to claim 1. 3. The method for synthesizing a substituted quinoline according to claim 1, wherein the cyclization reaction is allowed to proceed in a tetrahydrofuran solution in the presence of hydrochloric acid of 3 N or more.