Process for the preparation of quinoline compounds

Abstract

The application relates to the preparation field of quinoline compounds and discloses a method for preparing a quinoline compound shown in formula (I), which comprises the following steps: in the presence of inert high-boiling-point polyether solvents, substituting a compound shown in formula (III) with 3,5-dichloroaniline to obtain a compound shown in formula (II), and then performing ring closure reaction to obtain the compound shown in formula (I), wherein X1, X3, X4, X5 and X6 are each independently -CN or -COOR'; R' is C1-C4 alkyl; wherein X1 is same as at least one of X3, X4, X5 and X6; X3 and X4 are same or different, X5 and X6 are same or different; X2 is a hydroxyl group or an amino group; R1 and R2 are each independently hydrogen or C1-C4 alkyl; and R1 and R2 are same or different. The method has the advantages of low reaction temperature, low cost and high yield, and is beneficial to industrialization.

Description

Technical Field

[0001] This invention relates to the field of quinoline compounds preparation, and more specifically to a method for preparing quinoline compounds. Background Technology

[0002] There are few reported methods for preparing 5,7-dichloroquinoline compounds both domestically and internationally. Most methods involve a substitution reaction between 5,7-dichloroaniline and diethyl ethoxymethylene malonate, followed by high-temperature self-ring-closure. The problems with this approach are the long substitution reaction time and the need for continuous ethanol distillation to drive the reaction. Furthermore, diethyl ethoxymethylene malonate is prepared by reflux reaction of diethyl malonate and orthoformate, which is time-consuming, consumes large amounts of triorthoformate, and requires excess acetic anhydride for complete reaction, resulting in numerous byproducts, high energy consumption, and high costs, hindering industrial production. In recent years, efforts have been made to improve this type of reaction. For example, by controlling the reaction temperature, the polymerization of acrylic acid feedstock can be reduced. If the feedstock polymerizes, the reaction is almost non-existent or even stops. Moreover, prolonged reaction times generate large amounts of phosphoric acid wastewater, causing environmental pollution. The process is complex, and costs are consequently higher.

[0003] CN1246112A discloses a method for preparing 4-oxygen-substituted quinoline compounds. The method involves reacting aniline with dialkyl alkoxymethylene malonate to obtain an addition compound that has lost ethanol. This addition compound is then subjected to high-temperature self-cyclization to obtain the quinoline compound. However, the reaction temperature is limited by the amount of alcohol generated and the rate of alcohol removal during the reaction, increasing the difficulty of the reaction. Furthermore, the high price of dialkyl alkoxymethylene malonate leads to increased production costs, and the yield of the prepared quinoline compound is less than 95%.

[0004] In summary, existing methods for preparing 5,7-dichloroquinoline compounds suffer from technical problems such as low reaction yield and high cost. Therefore, there is a need to find a low-cost, high-yield method for preparing quinoline compounds. Summary of the Invention

[0005] The purpose of this invention is to overcome the technical problems of low reaction yield and high cost in the prior art, and to provide a method for preparing quinoline compounds, which has the advantages of low cost, high conversion rate and high selectivity.

[0006] To achieve the above objectives, the present invention provides a method for preparing quinoline compounds, the method comprising: reacting a compound of formula (III) with 3,5-dichloroaniline in the presence of an inert high-boiling-point polyether solvent to obtain a compound of formula (II), followed by a cyclization reaction to obtain a compound of formula (I).

[0007]

[0008] Wherein, X1, X3, X4, X5 and X6 are each independently -CN or -COOR', and R' is a C1-C4 alkyl group; wherein, X1 is the same as at least one of X3, X4, X5 and X6; X3 and X4 may be the same or different, and X5 and X6 may be the same or different;

[0009] X2 is a hydroxyl or amino group;

[0010] R1 and R2 are each independently hydrogen or C1-C4 alkyl groups; R1 and R2 may be the same or different.

[0011] Compared with the prior art, the present invention first undergoes a substitution reaction between the compound shown in formula (III) (i.e., an enamine compound) and 3,5-dichloroaniline to obtain the compound shown in formula (II), and then undergoes a cyclization reaction to obtain the compound shown in formula (I) (a quinoline compound). The method of the present invention has the advantages of lower reaction temperature, lower cost and higher yield, which is conducive to industrialization. Detailed Implementation

[0012] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0013] This invention provides a method for preparing quinoline compounds, the method comprising:

[0014]

[0015] In the presence of an inert, high-boiling-point polyether solvent, the compound shown in formula (III) was subjected to a substitution reaction with 3,5-dichloroaniline to give the compound shown in formula (II), followed by a cyclization reaction to give the compound shown in formula (I).

[0016]

[0017] Wherein, X1, X3, X4, X5 and X6 are each independently -CN or -COOR', and R' is a C1-C4 alkyl group; wherein, X1 is the same as at least one of X3, X4, X5 and X6; X3 and X4 may be the same or different, and X5 and X6 may be the same or different;

[0018] X2 is a hydroxyl or amino group;

[0019] R1 and R2 are each independently hydrogen or C1-C4 alkyl groups; R1 and R2 may be the same or different.

[0020] In this invention, preferably, X3 is the same as X5 or X6; or, X4 is the same as X5 or X6.

[0021] In this invention, preferably, X3, X4, X5 and X6 are all the same.

[0022] According to some embodiments of the present invention, in formula (III), at least one of R1 and R2 is selected from C1-C4 alkyl groups.

[0023] According to a preferred embodiment of the present invention, R1 is hydrogen, methyl, ethyl or propyl, and R2 is methyl, ethyl or propyl.

[0024] According to a preferred embodiment of the present invention, R1 is hydrogen or methyl, and R2 is methyl.

[0025] According to some embodiments of the present invention, R' is methyl or ethyl.

[0026] According to some embodiments of the present invention, the conditions for the substitution reaction may include: a temperature of 20-160°C, preferably 60-100°C; and a time of 30-120 min, preferably 30-50 min.

[0027] According to some embodiments of the present invention, in the substitution reaction, the amount of the compound represented by formula (III) can be 1-5 mol, preferably 1-1.5 mol, relative to 1 mol of 3,5-dichloroaniline.

[0028] According to some embodiments of the present invention, the conditions for the ring-closing reaction may include: a temperature of 120-230°C, preferably 140-180°C; and a time of 60-300 min, preferably 120-180 min.

[0029] According to some embodiments of the present invention, the inert high-boiling-point polyether solvent may be selected from at least one of diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, triethylene glycol diethyl ether and tetraethylene glycol dimethyl ether, preferably tetraethylene glycol dimethyl ether.

[0030] According to some embodiments of the present invention, in the substitution reaction, the amount of the inert high-boiling-point polyether solvent used can be 2-30 mL, preferably 5-15 mL, relative to each gram of 3,5-dichloroaniline.

[0031] In this invention, the boiling point of the inert high-boiling-point polyether solvent can be 150-300℃, preferably 200-300℃.

[0032] According to some embodiments of the present invention, both the substitution reaction and the cyclization reaction can be carried out under an inert atmosphere; the inert atmosphere is preferably provided by nitrogen.

[0033] In this invention, the compound represented by formula (III) (e.g., formula (IIIa)) can be obtained commercially or prepared by the following steps:

[0034] 1) React dimethyl sulfate with N,N-dimethylformamide (DMF) at 60-70℃ for 1-5 hours to obtain an imine complex, which is then stored at -5 to 0℃ for later use.

[0035] 2) At 30-50°C, diethyl malonate is contacted with the imine complex obtained in step 1), and an organic base (e.g., diisopropylethylamine (DIPEA) or triethylamine (TEA)) is added to the reaction system under an inert atmosphere to prepare the compound shown in formula (IIIa); wherein, the organic base is preferably added in a form soluble in an organic solvent (e.g., toluene); and the inert atmosphere is preferably nitrogen.

[0036] The present invention will be described in detail below through embodiments.

[0037] In the following examples, liquid chromatography (HPLC) was used for monitoring: Agilent HPLC 1260; unless otherwise specified, all raw materials used were commercially available products. The reaction products of each step were analyzed by... 1 The structure was verified by H-NMR (400M); the conversion and selectivity (based on the compound shown in formula (III)) were obtained by normalized numerical calculation by HPLC.

[0038] The following preparation is used for the compound shown in formula (III)

[0039] Preparation Example 1

[0040]

[0041] 1) Add 289g (3.96mol) of DMF to a 2L reaction flask, and add 450g (3.57mol) of dimethyl sulfate dropwise while stirring at 70℃. After the addition is completed, the reaction is carried out at 70℃ for 3 hours to obtain an imine complex. Cool the complex to below 0℃ in an ice bath and set aside for later use.

[0042] In a 2L four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 160g (1mol) of diethyl malonate and 1.5mol of the imine complex prepared in step 1) were added. The mixture was stirred until fully combined, and nitrogen gas was introduced for protection. A toluene solution (300mL) containing 1.5mol of diisopropylethylamine (DIPEA) was added dropwise to the reaction system. The reaction was carried out at 40°C for 2 hours. The reaction was monitored by HPLC until completion. Toluene was distilled off under reduced pressure, and the final product was purified by column chromatography to obtain compound (IIIa). The final conversion rate was 99%, and the selectivity was 98%.

[0043] Preparation Example 2

[0044]

[0045] The preparation was carried out in the same manner as in Example 1, except that dimethyl malonate was used instead of diethyl malonate, with a conversion rate of 99% and a selectivity of 98%.

[0046] Preparation Example 3

[0047]

[0048] The preparation was carried out in the same manner as in Example 1, except that ethyl cyanoacetate was used instead of diethyl malonate, with a conversion rate of 99% and a selectivity of 98%.

[0049] Preparation Example 4

[0050]

[0051] The preparation was carried out in the same manner as in Example 1, except that methyl cyanoacetate was used instead of diethyl malonate, with a conversion rate of 99% and a selectivity of 98%.

[0052] Preparation Example 5

[0053]

[0054] The preparation was carried out in the same manner as in Example 1, except that malondicyanate was used instead of diethyl malonate, with a conversion rate of 99% and a selectivity of 98%.

[0055] Preparation Example 6

[0056]

[0057] The preparation was carried out in the same manner as in Example 1, except that the complex of DMF dimethyl sulfate was replaced with the complex of N-methylformamide dimethyl sulfate, with a conversion rate of 99% and a selectivity of 98%.

[0058] Preparation Example 7

[0059]

[0060] The preparation was carried out in the same manner as in Example 1, except that TEA was used instead of DIPEA, with a conversion rate of 96% and a selectivity of 98%.

[0061] The following examples are used to prepare the compound shown in formula (I).

[0062] Example 1

[0063] In a 500 mL three-necked round-bottom flask equipped with a short-diameter distillation head, 24.4 g (0.15 mol) of 3,5-dichloroaniline, 33.97 g (0.158 mol) of the compound of formula (IIIa) obtained in Preparation Example 1, and 200 mL of tetraethylene glycol dimethyl ether were added sequentially with mechanical stirring. The mixture was thoroughly stirred, and while purging the top of the flask with nitrogen, the reaction system was heated to 80 °C to remove the dimethylamine gas generated by the substitution reaction. The reaction time was 40 min, and the reaction was monitored by HPLC to ensure complete reaction, yielding the compound of formula (IIa). Nitrogen was continuously purged from the top, and the temperature was increased to 150 °C to induce a ring-closure reaction in the compound of formula (IIa) and remove ethanol generated during the reaction. The reaction was carried out for 120 min, and the reaction was monitored by HPLC to ensure complete reaction, yielding the target compound (the compound of formula (Ia), see Table 1), with a conversion rate of 97% and a selectivity of 98%.

[0064] Examples 2-7 were carried out in the same manner as Example 1, except that the compounds (enamine compounds) of formula (III) obtained in Preparation Examples 2-7 were used instead of the compounds of formula (III) obtained in Preparation Example 1 to synthesize compounds of formula (Ib)-(Ie) (see Table 1).

[0065] Table 1

[0066]

[0067] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing quinoline compounds of formula (I), characterized in that, The method includes: Formula (I) In the presence of an inert, high-boiling-point polyether solvent, the compound shown in formula (III) was subjected to a substitution reaction with 3,5-dichloroaniline to give the compound shown in formula (II), which was then subjected to a cyclization reaction to give the compound shown in formula (I). Formula (III) Formula (II); Wherein, X2 is a hydroxyl group, X1, X3, X4, X5 and X6 are -COOR', and R' is a C1-C4 alkyl group; Alternatively, X2 is an amino group, and X1, X3, X4, X5, and X6 are -CN; R1 and R2 are methyl groups; The conditions for the substitution reaction include: a temperature of 60-80℃ and a time of 30-50 min; The conditions for the ring-closing reaction include: a temperature of 140-180℃ and a time of 120-180 min.

2. The method according to claim 1, wherein, R' is methyl or ethyl.

3. The method according to claim 1, wherein, In the substitution reaction, the amount of the compound represented by formula (III) is 1-1.5 mol relative to 1 mol of 3,5-dichloroaniline.

4. The method according to any one of claims 1-3, wherein, The inert high-boiling-point polyether solvent is selected from at least one of diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, and tetraethylene glycol dimethyl ether.

5. The method according to claim 4, wherein, The inert high-boiling-point polyether solvent is tetraethylene glycol dimethyl ether.

6. The method according to any one of claims 1-3, wherein, In the substitution reaction, the amount of the inert high-boiling polyether solvent used is 2-30 mL relative to each gram of 3,5-dichloroaniline.

7. The method according to claim 6, wherein, In the substitution reaction, the amount of the inert high-boiling polyether solvent used is 5-15 mL relative to each gram of 3,5-dichloroaniline.

8. The method according to any one of claims 1-3, wherein, Both the substitution reaction and the cyclization reaction were carried out under an inert atmosphere.

9. The method according to claim 8, wherein, The inert atmosphere is provided by nitrogen.

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