An intermediate compound for preparing distilled water and its preparation method, and a preparation method of distilled water

Abstract

The invention discloses an intermediate compound BXJ05 for preparing distilled water and a preparation method thereof; also discloses an intermediate compound BXJ06 for preparing distilled water based on the compound BXJ05 and a preparation method thereof; and also discloses a method for preparing distilled water based on the compound BXJ06. The preparation method uses 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde (compound BXJ04) as a starting raw material, and obtains the intermediate compound BXJ05 through an etherification reaction; uses the compound BXJ05 as a raw material, and obtains the intermediate compound BXJ06 through a cyclization followed by decarboxylation; and uses the compound BXJ06 as a raw material, and finally obtains the final product distilled water through a methoxylation reaction. The synthesis process is simple in each reaction step, can significantly improve the yield of the final product distilled water, and is suitable for industrial application.

Description

Technical Field

[0001] The present application belongs to the field of preparation of distilled water, and in particular relates to an intermediate compound for preparing distilled water, a preparation method thereof, and a preparation method of distilled water. Background Art

[0002] Dictamidine, also known as dichloroamine, belongs to the furanoquinoline alkaloids and is an active ingredient isolated from the root bark of the Rutaceae plant Dictamni. Its structural formula is shown in the following formula (III):

[0003]

[0004] Modern pharmacological studies have shown that distilled water has multiple good medicinal values such as antibacterial, anti-inflammatory, antimicrobial, and anticancer. Distilled water can inhibit Candida albicans, and distilled water and fluconazole have good synergy, and drug combination can improve the therapeutic effect of antifungal drugs and reduce the toxicity of drugs. In addition, distilled water has good anti-inflammatory effects and can significantly reduce the swelling degree of the mouse auricle caused by xylene. Distilled water can also be used as a natural food preservative, and it has antimicrobial activity.

[0005] Currently, the main way to obtain difficile is through extraction, which uses organic solvents to extract the root bark of the Chinese herbal medicine Dictamnus to obtain a total extract, which is then separated and purified by chromatography. The purification process using extraction is relatively cumbersome and requires a large amount of Dictamnus root bark.

[0006] There are relatively few reports on the artificial synthesis of dichloroquine, and the yields are generally low. The reaction conditions are demanding and difficult to meet the requirements for industrial application. For example, Narasimhan et al. (Tetrahedron, 1974, 30(23):4153-7.) reported that dichloroquine was synthesized by first synthesizing 2,4-dichloroquinoline and then through methoxylation, lithiation, substitution, condensation, hydrolysis, and cyclization, as shown below:

[0007]

[0008] The main drawbacks of this route are the high consumption of phosphorus oxychloride and the difficulty of post-processing. Furthermore, the strong base n-butyl lithium is required, which creates demanding reaction conditions. The multi-step reaction requires column chromatography purification, which increases time and material costs, resulting in low overall yields and high costs, making it unsuitable for industrial application.

[0009] For example, Long Jun et al. (Synthetic Chemistry, 2008, (01): 118-9+22) reported the synthesis of daunoline using aniline as the starting material through five steps of substitution, ring closure, methylation, reduction, and elimination, as shown below:

[0010]

[0011] This route requires the use of diazomethane, a highly toxic gas that is dangerous and poses an explosion risk for large-scale industrial use. The cyclization reaction requires high temperatures of 250°C, placing high demands on equipment and operation. Furthermore, the residue produced by the sodium borohydride reduction reaction is difficult to post-process, making it unsuitable for industrial application.

[0012] Therefore, there is an urgent need for a preparation process for distilled soda ash that is suitable for industrial production and application, safe, and has a high yield. Summary of the Invention

[0013] Objectives of the invention: The first objective of the present invention is to provide an intermediate compound BXJ05 for preparing distilled water and a preparation method thereof; the second objective of the present invention is to provide an intermediate compound BXJ06 for preparing distilled water based on compound BXJ05 and a preparation method thereof; the third objective of the present invention is a method for preparing distilled water based on compound BXJ06, which is suitable for industrial production applications, is safe, and has a high yield.

[0014] Technical solution: The present invention is used to prepare an intermediate compound of daunoline, the structural formula of which is shown in the following formula (I):

[0015]

[0016] The method of the present invention for preparing the intermediate compound comprises the following steps: conducting an etherification reaction between compound BXJ04 and haloacetic acid Y01 in a molar ratio of 1:1-6 in an aqueous solution in the presence of an inorganic base to obtain compound BXJ05;

[0017]

[0018] Wherein, X in the halogenated acetic acid Y01 structure is selected from Cl, Br or I.

[0019] Preferably, X in the structure of the haloacetic acid Y01 used in the preparation method can be selected from Cl.

[0020] Preferably, the molar ratio of compound BXJ04 to haloacetic acid Y01 is 1:1.69-3.

[0021] Furthermore, the molar ratio of compound BXJ04 to the inorganic base used in the preparation method is 1:1-4, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide. The inorganic base is preferably sodium hydroxide. The molar ratio of compound BXJ04 to the inorganic base is preferably 1:2.

[0022] The present invention is used to prepare an intermediate compound of daunoline, and the structural formula of the compound is shown in the following formula (II):

[0023]

[0024] The method for preparing the intermediate compound of the present invention comprises the following steps: cyclizing compound BXJ05 in the presence of sodium acetate, acetic acid and acetic anhydride, followed by decarboxylation to obtain compound BXJ06; wherein the molar ratio of compound BXJ05 to sodium acetate is 1:2-9, the molar ratio of compound BXJ05 to acetic acid is 1:15-25, and the molar ratio of compound BXJ05 to acetic anhydride is 1:10-20;

[0025]

[0026] Preferably, the molar ratio of compound BXJ05 to sodium acetate is 1:3-6, the molar ratio of compound BXJ05 to acetic acid is 1:15-21, and the molar ratio of compound BXJ05 to acetic anhydride is 1:10-14.

[0027] The method for preparing distilled water comprises the following steps: subjecting a compound BXJ06 to a methoxylation reaction in a methanol solution of sodium methoxide to prepare distilled water (III); wherein the molar ratio of the compound BXJ06 to the sodium methoxide is 1:1-4;

[0028]

[0029] Preferably, the molar ratio of compound BXJ06 to sodium methoxide can be 1:2-3.

[0030] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the distilled water alkaloid is prepared from 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde (BXJ04) as a starting material, and an intermediate compound BXJ05 is prepared through an etherification reaction; the intermediate compound BXJ06 is prepared through a cyclization reaction followed by decarboxylation using the compound BXJ05 as a raw material; and the final product distilled water alkaloid is prepared through a methoxylation reaction using the compound BXJ06 as a raw material. Each step of the reaction in the synthesis process is simple to operate, and the yield of the final product distilled water alkaloid can be significantly improved.

[0031] In addition, the reagents used in this synthesis method are less toxic, avoiding the use of diazomethane, and have low labor protection requirements. The reaction conditions are relatively mild, avoiding high temperature conditions such as 250°C, significantly reducing production costs and production risks. The amount of solvent used in each step of the reaction is very small, reducing solvent recovery operations and significantly reducing costs. The post-reaction treatment of each step of the route is simple, eliminating column chromatography operations, significantly reducing time and material costs, and achieving a high overall yield and strong operability, making it more suitable for industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the hydrogen spectrum of the daunorubicin prepared by the present invention. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further described in detail below with reference to the embodiments.

[0034] It should be noted that the starting material BXJ04 used in the present invention can be obtained by self-production, and the self-production method can be prepared by any method known in the art. For example, Song Liqiang et al. (Modern Medicine and Clinic, 2014, 29(10):1083-5.) reported a synthesis method of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde as follows. The synthesis process route of BXJ04 is mature, easy to operate, high in yield, low in cost, and can be produced and used in large quantities.

[0035]

[0036] Except for the above-mentioned starting material BXJ04, other raw materials used in the synthesis process of daunorubicin and its intermediates of the present invention can be directly purchased from the market.

[0037] Example 1-1 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid (Compound BXJ05)

[0038]

[0039] A solution (10 M) of 38.5 g (963.3 mmol) of sodium hydroxide in 96.3 ml of distilled water was added to a mixture of 100 g (481.7 mmol) of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (compound BXJ04), 77 g (814.9 mmol) of chloroacetic acid, and 600 ml of water; the mixture was slowly stirred and heated to boiling, and the resulting solution was heated under reflux for 3 hours; the solution was acidified with 190 ml of concentrated hydrochloric acid (specific gravity 1.19), filtered, and the precipitated product was collected on a Buchner funnel and rinsed with water. The light brown solid weighed 99 g and the molar yield was 77.3%.

[0040] 1 H NMR (300MHz, DMSO-d6) δ13.60(s,1H),10.29(s,1H),7.93(dd,J=8.2,1.5Hz,1H),7.65(ddd,J=8.4,7.1,1.5Hz,1H),7.42–7.13(m,2H),4.87(s,2H).

[0041] Example 1-2 4-Chlorofuran[2,3-b]quinoline (Compound BXJ06)

[0042]

[0043] In a 2 L flask, a mixture of 100 g (376.4 mmol) of dry crude 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid, 92.6 g (1.13 mol) of anhydrous powdered sodium acetate, 353.5 ml (3.764 mol) of acetic anhydride, and 322.9 ml (5.65 mol) of glacial acetic acid was refluxed at 150° C. for 8 h. The hot black solution was poured into 2 L of ice water and then extracted with 600 ml of ether. The ether layer was washed with water and then with cold 5% sodium hydroxide solution until the aqueous layer became alkaline. The ether layer was washed with water and then with saturated sodium chloride solution, and dried over anhydrous granular sodium sulfate. The ether was removed in a water bath to obtain 60 g of the product in a molar yield of 78.3%.

[0044] 1 HNMR (300MHz, DMSO-d6) δ8.31 (dd, J=8.3, 1.5Hz, 1H), 8.12 (d, J=2.8Hz, 1H), 7. 92(dd,J=8.4,1.5Hz,1H),7.68(ddd,J=8.3,6.9,1.5Hz,1H),7.55–7.43(m,2H).

[0045] Example 1-3 4-Methoxyfuran[2,3-b]quinoline (furanine, formula (III))

[0046]

[0047] Under argon protection, 500 ml of methanol was added to a 2L three-necked flask, 60 g (294.6 mmol) of 4-chlorofuran [2,3-b] quinoline was added to the methanol, and 106 ml (589.3 mmol) of a 30% sodium methoxide methanol solution was slowly added with stirring. The reaction solution was heated to 80 ° C and reacted for 6 hours. The reaction was detected until the raw materials were completely reacted; the reaction solution was cooled to room temperature, poured into 2L of ice water, stirred for 1 hour, filtered, washed with ice water, and dried to obtain 49 g of white solid 4-methoxyfuran [2,3-b] quinoline, the final product, white caustic soda, with a molar yield of 83.4% and a purity of 98.2%. The nuclear magnetic hydrogen spectrum was as follows Figure 1 As shown. The total yield of dapoxetine synthesized from 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde via three-step reactions of etherification, cyclization, decarboxylation, and methoxylation was 50.4%.

[0048] 1H NMR (300MHz, DMSO-d6) δ8.22 (dd, J=8.6, 1.5Hz, 1H), 8.06 (d, J=2.8Hz, 1H), 7.90 (dd, J=8.6,1.3Hz,1H),7.72(ddd,J=8.4,6.8,1.5Hz,1H),7.55–7.43(m,2H),4.45(s,3H).

[0049] Example 2-1 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid (Compound BXJ05)

[0050]

[0051] A solution (10 M) of 38.5 g (963.3 mmol) of sodium hydroxide in 96.3 ml of distilled water was added to a mixture of 100 g (481.7 mmol) of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (compound BXJ04), 91.0 g (963.3 mmol) of chloroacetic acid, and 600 ml of water; the mixture was slowly stirred and heated to boiling, and the resulting solution was heated under reflux for 3 hours; the solution was acidified with 190 ml of concentrated hydrochloric acid (specific gravity 1.19), filtered, and the precipitated product was collected on a Buchner funnel and rinsed with water. The light brown solid weighed 101 g and the molar yield was 78.9%.

[0052] 1 H NMR (300MHz, DMSO-d6) δ13.60(s,1H),10.29(s,1H),7.93(dd,J=8.2,1.5Hz,1H),7.65(ddd,J=8.4,7.1,1.5Hz,1H),7.42–7.13(m,2H),4.87(s,2H).

[0053] Example 2-2 4-Chlorofuran[2,3-b]quinoline (Compound BXJ06)

[0054]

[0055] In a 2 L flask, a mixture of 100 g (376.4 mmol) of dry crude 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid, 135.9 g (1.66 mol) of anhydrous powdered sodium acetate, 424.3 ml (4.52 mol) of acetic anhydride, and 387.5 ml (6.78 mol) of glacial acetic acid was refluxed at 150° C. for 8 h. The hot black solution was poured into 2 L of ice water and then extracted with 600 ml of ether. The ether layer was washed with water and then with cold 5% sodium hydroxide solution until the aqueous layer became alkaline. The ether layer was washed with water and then with saturated sodium chloride solution, and dried over anhydrous granular sodium sulfate. The ether was removed in a water bath to obtain 61.5 g of the product in a molar yield of 80.2%.

[0056] 1HNMR (300MHz, DMSO-d6) δ8.31 (dd, J=8.3, 1.5Hz, 1H), 8.12 (d, J=2.8Hz, 1H), 7. 92(dd,J=8.4,1.5Hz,1H),7.68(ddd,J=8.3,6.9,1.5Hz,1H),7.55–7.43(m,2H).

[0057] Example 2-3 4-Methoxyfurano[2,3-b]quinoline (furanine, formula (III))

[0058]

[0059] Under argon, 500 ml of methanol was added to a 2-L three-necked flask. 60 g (294.6 mmol) of 4-chlorofurano[2,3-b]quinoline was added to the methanol. With stirring, 132.7 g (736.7 mmol) of a 30% sodium methoxide solution in methanol was slowly added. The reaction solution was heated to 80°C and allowed to react for 6 hours. The reaction was monitored until the reaction was complete. The reaction solution was cooled to room temperature, poured into 2 L of ice water, stirred for 1 hour, filtered, washed with ice water, and dried to obtain 49.5 g of 4-methoxyfurano[2,3-b]quinoline (the final product, dapoxetine) as a white solid with a molar yield of 84.3% and a purity of 98.2%. Dapoxetine was synthesized from 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde via a three-step reaction of etherification, cyclization, decarboxylation, and methoxylation, resulting in a total yield of 53.3%.

[0060] 1 H NMR (300MHz, DMSO-d6) δ8.22 (dd, J=8.6, 1.5Hz, 1H), 8.06 (d, J=2.8Hz, 1H), 7.90 (dd, J=8.6,1.3Hz,1H),7.72(ddd,J=8.4,6.8,1.5Hz,1H),7.55–7.43(m,2H),4.45(s,3H).

[0061] Example 3-1 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid (Compound BXJ05)

[0062]

[0063] A solution (10 M) of 38.5 g (963.3 mmol) of sodium hydroxide in 96.3 ml of distilled water was added to a mixture of 100 g (481.7 mmol) of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (compound BXJ04), 136.5 g (1.44 mol) of chloroacetic acid, and 600 ml of water; the mixture was slowly stirred and heated to boiling, and the resulting solution was heated under reflux for 3 hours; the solution was acidified with 190 ml of concentrated hydrochloric acid (specific gravity 1.19), filtered, and the precipitated product was collected on a Buchner funnel and rinsed with water. The light brown solid weighed 105 g and the molar yield was 82.1%.

[0064] 1 H NMR (300MHz, DMSO-d6) δ13.60(s,1H),10.29(s,1H),7.93(dd,J=8.2,1.5Hz,1H),7.65(ddd,J=8.4,7.1,1.5Hz,1H),7.42–7.13(m,2H),4.87(s,2H).

[0065] Example 3-2 4-Chlorofuran[2,3-b]quinoline (Compound BXJ06)

[0066]

[0067] In a 2 L flask, a mixture of 100 g (376.4 mmol) of dry crude 2-((4-chloro-3-formylquinolin-2-yl)oxy)acetic acid, 185.3 g (2.26 mol) of anhydrous powdered sodium acetate, 495.0 ml (5.27 mol) of acetic anhydride, and 452.1 ml (7.91 mol) of glacial acetic acid was refluxed at 150° C. for 8 h. The hot black solution was poured into 2 L of ice water and then extracted with 600 ml of ether. The ether layer was washed with water and then with cold 5% sodium hydroxide solution until the aqueous layer became alkaline. The ether layer was washed sequentially with water and saturated sodium chloride solution and dried over anhydrous granular sodium sulfate. The ether was removed in a water bath to obtain 58 g of the product in a molar yield of 75.7%.

[0068] 1HNMR (300MHz, DMSO-d6) δ8.31 (dd, J=8.3, 1.5Hz, 1H), 8.12 (d, J=2.8Hz, 1H), 7. 92(dd,J=8.4,1.5Hz,1H),7.68(ddd,J=8.3,6.9,1.5Hz,1H),7.55–7.43(m,2H).

[0069] Example 3-3 4-Methoxyfuran[2,3-b]quinoline (furanine, formula (III))

[0070]

[0071] Under argon, 500 ml of methanol was added to a 2-L three-necked flask. 60 g (294.6 mmol) of 4-chlorofurano[2,3-b]quinoline was added to the methanol. With stirring, 159.1 g (884.0 mmol) of a 30% sodium methoxide solution in methanol was slowly added. The reaction solution was heated to 80°C and allowed to react for 6 hours. The reaction was monitored until the reaction was complete. The reaction solution was cooled to room temperature, poured into 2 L of ice water, stirred for 1 hour, filtered, washed with ice water, and dried to obtain 51 g of 4-methoxyfurano[2,3-b]quinoline as a white solid, with a molar yield of 86.9% and a purity of 98.2%. The total yield of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxaldehyde was 54.0%. The reaction was synthesized in three steps: etherification, cyclization, decarboxylation, and methoxylation.

[0072] 1H NMR (300MHz, DMSO-d6) δ8.22 (dd, J=8.6, 1.5Hz, 1H), 8.06 (d, J=2.8Hz, 1H), 7.90 (dd, J=8.6,1.3Hz,1H),7.72(ddd,J=8.4,6.8,1.5Hz,1H),7.55–7.43(m,2H),4.45(s,3H).

[0073] In addition to the above, X in the haloacetic acid Y01 structure used in the preparation of compound BXJ05 of the present invention can also be selected from Br or I, and the inorganic base used can also be potassium hydroxide or lithium hydroxide. Compound BXJ05 can also be prepared by a molar ratio of compound BXJ04 to haloacetic acid Y01 within the range of 1:1-6 and a molar ratio of compound BXJ04 to inorganic base within the range of 1:1-4.

[0074] Compound BXJ06 can also be prepared by using a molar ratio of compound BXJ05 to sodium acetate within the range of 1:2-9, a molar ratio of compound BXJ05 to acetic acid within the range of 1:15-25, and a molar ratio of compound BXJ05 to acetic anhydride within the range of 1:10-20.

[0075] When preparing distilled water (III), the molar ratio of compound BXJ06 to sodium methoxide used is within the range of 1:1-4 to prepare distilled water (III).

Claims

1. A method for preparing distilled water, characterized in that: The method comprises the following steps: subjecting a compound BXJ06 to a methoxylation reaction in a methanol solution of sodium methoxide to prepare daunoline (III); wherein the molar ratio of the compound BXJ06 to the sodium methoxide is 1:1-4; The preparation method of compound BXJ06 is to cyclize compound BXJ05 in the presence of sodium acetate, acetic acid and acetic anhydride and then decarboxylate it; wherein the molar ratio of compound BXJ05 to sodium acetate is 1:2-9, the molar ratio of compound BXJ05 to acetic acid is 1:15-25, and the molar ratio of compound BXJ05 to acetic anhydride is 1:10-20; The preparation method of compound BXJ05 is to carry out etherification reaction of compound BXJ04 and haloacetic acid Y01 in a molar ratio of 1:1-6 in an aqueous solution in the presence of an inorganic base; Wherein, X in the halogenated acetic acid Y01 structure is selected from Cl, Br or I.

2. The method for preparing distilled water according to claim 1, wherein X in the haloacetic acid Y01 structure is selected from Cl.

3. The method for preparing distilled water according to claim 1, wherein The molar ratio of the compound BXJ04 to the inorganic base is 1:1-4, and the inorganic base is sodium hydroxide, potassium hydroxide or lithium hydroxide.

4. The method for preparing distilled water according to claim 3, wherein: The inorganic base is sodium hydroxide.

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