Synthesis method of 5, 6-dimethoxy isoindoline hydrochloride

Abstract

The invention relates to a synthesis method of 5, 6-dimethoxy isoindoline hydrochloride. The synthesis method comprises a compound formula (I), a compound formula (II), a compound formula (III) and a compound formula (IV). The specific synthesis route is as follows: # imgabs 0 #: Friedel-Crafts acylation of formaldehyde is performed on a compound shown in a formula (I) in the step 1) under the condition of a reaction solvent, dihalide is generated in the presence of a hydrogen halide solution, and a compound shown in a formula (II) is obtained; 2) reacting the compound as shown in the formula (II) with an amine reagent, potassium iodide and alkali in the presence of a reaction solvent to obtain a compound as shown in a formula (III); and 3) reacting the compound as shown in the formula (III) with chloroformic acid-1-chloroethyl ester in the presence of a reaction solvent for debenzylation to obtain a compound as shown in a formula (IV). The method has the advantages that the synthesis path is simple, the reaction process is controllable, and the difficulty of generation of byproducts and subsequent purification is reduced. The yield and the purity of the target product are remarkably improved by accurately controlling the reaction conditions and the molar ratio; the raw materials used in the technological process are cheap, an expensive palladium catalyst is not used, the cost is remarkably reduced, and the method is suitable for the requirements of large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, in particular to a method for synthesizing 5,6-dimethoxyisoindoline hydrochloride. Background Art

[0002] Indole compounds have broad application prospects in the field of medicine. 5,6-Dimethoxyisoindoline hydrochloride and its derivatives, as indole compounds, have unique biological activities, such as antibacterial, anti-inflammatory, and anti-tumor. Therefore, it is often used as an intermediate or raw material for the synthesis of new drugs.

[0003] According to the literature report of J.Med.Chem.1999,42,2145-2161, the synthesis of 5,6-dimethoxyindoline mainly uses 1-methoxy-2-(phenylmethoxy)benzene, polyformaldehyde, ZnI 2 , HCl gas, benzylamine, (Bu)4NCl, Pd(OH)2 / C as raw materials, through the Friedel-Crafts acylation of polyformaldehyde, dichloride is produced in the presence of hydrochloric acid; then it reacts with benzylamine, and then it is reduced and hydrogenated by palladium hydroxide on carbon to obtain 5,6-dimethoxyindoline. However, the process has a low yield and requires the use of catalyst palladium hydroxide, which is expensive and limits the development of the industry. The reaction formula is as follows:

[0004]

[0005] According to the literature J.Med.Chem.2016, 59, 3, 934-946 and WO 2013 / 039854, the synthesis of 5,6-dimethoxyindoline mainly uses o-phenylenedimethyl ether as raw material, HBr, triphenylamine, DIEA, and TFA as raw materials, and produces dichloride in the presence of HBr through Friedel-Crafts acylation of polyformaldehyde; then reacts with benzylamine, and then debenzylates with TFA to obtain 5,6-dimethoxyindoline. However, the process yield is low, and triphenylamine is required, which increases the cost. The reaction formula is as follows:

[0006]

[0007] Based on the above research status, how to provide a high-yield and low-cost preparation method of 5,6-dimethoxyisoindoline hydrochloride to solve the problems of low yield and high production cost of the above process has become a technical problem that the present invention urgently needs to solve. Summary of the invention

[0008] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing 5,6-dimethoxyisoindoline hydrochloride, wherein the synthetic route is simple, the reaction process is controllable, and the difficulty of by-product generation and subsequent purification is reduced. The yield and purity of the target product are significantly improved by accurately controlling the reaction conditions and the molar ratio; the raw materials used in the process are cheap, and no expensive palladium catalyst is used, which significantly reduces the cost and is suitable for the needs of large-scale industrial production.

[0009] The present invention is achieved through the following technical scheme: On the one hand, a method for synthesizing 5,6-dimethoxyisoindoline hydrochloride is provided, and the method comprises compound formula (I), compound formula (II), compound formula (III), and compound formula (IV); the specific synthesis path is as follows:

[0010]

[0011] R 1 =Cl, Br, etc.

[0012] R 2 =PMB, Bn, etc.

[0013] Step 1) The compound represented by formula (I) is subjected to Friedel-Crafts acylation of formaldehyde in a reaction solvent to generate a dihalide in the presence of a hydrogen halide solution to obtain a compound represented by formula (II);

[0014] Step 2) the compound represented by formula (II) reacts with an amine reagent, potassium iodide and a base in a reaction solvent to obtain a compound represented by formula (III);

[0015] Step 3) The compound represented by formula (III) is debenzylated by reacting with 1-chloroethyl chloroformate in a reaction solvent to obtain a compound represented by formula (IV).

[0016] Furthermore, in step 1), the molar ratio of the formaldehyde to the compound represented by formula (I) is 3-5:1

[0017] Furthermore, in step 1), the hydrogen halide is selected from any one of HCl and HBr; the molar ratio of the hydrogen halide to the compound represented by formula (I) is 3-5:1.

[0018] Furthermore, in step 2), the amine reagent is selected from any one of p-methoxybenzylamine and benzylamine; the molar ratio of the amine reagent to the compound represented by formula (II) is (1.2-2):1; preferably 2:1.

[0019] Furthermore, in step 2), the molar ratio of KI to the compound represented by formula (II) is (0.1-0.5):1; preferably 0.5:1.

[0020] Furthermore, in step 2), the base is selected from any one of sodium bicarbonate and sodium tert-butoxide; the molar ratio of the base to the compound represented by formula (II) is (1.5-3):1; preferably 3:1.

[0021] Furthermore, in step 3), the molar ratio of the 1-chloroethyl chloroformate to the compound represented by formula (III) is (1.2-2):1; preferably 2:1.

[0022] Furthermore, in step 3), dioxane hydrochloride is also added, and the molar ratio of dioxane hydrochloride to the compound represented by formula (III) is (1.2-2):1; preferably 2:1.

[0023] Furthermore, in step 1) to step 2), the reaction solvent is any one of THF and DMF; the ratio of the reaction solvent to the compound represented by formula (I) / formula (II) is (5-20) mL:1 g, preferably 20 mL:1 g.

[0024] Further, in step 3), the reaction solvent is a MeOH / DCM mixed solution, and the volume ratio of MeOH to DCM in the mixed solution is (1-10):1; preferably 10:1.

[0025] Beneficial Effects

[0026] ① The present invention ensures efficient reaction by precisely controlling reaction conditions and molar ratio, improves the yield and purity of the target product, effectively reduces the generation of by-products, and reduces the difficulty and cost of subsequent purification.

[0027] ② The synthesis route of the present invention is simple, the reaction process is controllable, and a complicated post-processing process is avoided.

[0028] ③ The raw materials used in the process are cheap and easily available, and no expensive palladium catalyst is used, which significantly reduces the cost and is suitable for the needs of large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the 1HNMR spectrum of 5,6-dimethoxyisoindoline hydrochloride;

[0030] Figure 2 This is the LC spectrum of 5,6-dimethoxyisoindoline hydrochloride. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0032] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The experimental methods without specific conditions in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions or parts are by weight.

[0033] Unless otherwise specified, the reagents and raw materials used in the examples and comparative examples of the present invention can be obtained through commercial channels.

[0034] Example 1

[0035] A preparation method of 5,6-dimethoxyisoindoline hydrochloride

[0036]

[0037] 1) At room temperature, add 100g of the compound represented by formula (I) to 1L THF, then add 294mL 37% formaldehyde solution and 302mL concentrated hydrochloric acid (12N) respectively, stir at room temperature for 20h, detect the reaction by TLC, then heat the mixture to 65℃ and stir for 1h, and then cool to 0℃. Collect the precipitated solid by filtration, wash with cooled HOAc, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, column chromatography, and obtain 146g of the compound represented by formula (II), with a yield of 86%. In this embodiment, the molar ratio of the compound represented by formula (I), 37% formaldehyde solution, and concentrated hydrochloric acid is 1:5:5.

[0038] 2) Dissolve 146g of the compound represented by formula (II) in 1.46L DMF, add 172g of p-methoxybenzylamine, 47g of potassium iodide and 131g of sodium bicarbonate, react at 40°C for 5h, detect the reaction by TLC, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, column chromatography, and obtain 177g of the compound represented by formula (III), with a yield of 95%. In this embodiment, the molar ratio of the compound represented by formula (II), p-methoxybenzylamine, potassium iodide and sodium bicarbonate is 1:2:0.2:2.5.

[0039] 3) Dissolve 177g of the compound shown in formula (III) in 1.77L MeOH / DCM mixed solution, keep it at 0℃, slowly add 169g 1-chloroethyl chloroformate, and then heat the mixture under reflux for 3h. The reaction is complete when detected by TLC. Extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, add 885mL 1.4-dioxane to the product after column chromatography concentration, dissolve it, then add 296mL dioxane hydrochloride (4N) and stir for 1h, filter after solid precipitation, wash with dioxane, and dry to obtain 125g of the compound shown in formula (IV), with a yield of 98%. In this embodiment, the molar ratio of the compound shown in formula (III), 1-chloroethyl chloroformate, and dioxane hydrochloride is 1:2:2.

[0040] Example 2

[0041] 1) At room temperature, add 100g of the compound represented by formula (I) to 1L THF, then add 294mL 37% formaldehyde solution and 181mL concentrated hydrochloric acid (12N) respectively, stir at room temperature for 20h, and detect the reaction by TLC. Then heat the mixture to 65℃ and stir for 1h, and then cool to 0℃. Collect the precipitated solid by filtration, wash with cooled HOAc, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 145g of the compound represented by formula (II), with a yield of 85%. In this embodiment, the molar ratio of the compound represented by formula (I), 37% formaldehyde solution, and concentrated hydrochloric acid is 1:3:5.

[0042] 2) Dissolve 146g of the compound represented by formula (II) in 1.46L DMF, add 172g of p-methoxybenzylamine, 9g of potassium iodide and 148g of sodium tert-butoxide, react at 40°C for 5h, detect the reaction by TLC, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, column chromatography, and obtain 172g of the compound represented by formula (III), with a yield of 93.5%. In this embodiment, the molar ratio of the compound represented by formula (II), p-methoxybenzylamine, potassium iodide and sodium bicarbonate is 1:2:0.1:2.5.

[0043] 3) Dissolve 172g of the compound shown in formula (III) in 1.72L MeOH / DCM mixed solution, keep it at 0°C, slowly add 164g 1-chloroethyl chloroformate, and then heat the mixture under reflux for 3h. The reaction is complete when detected by TLC. Extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, add 861mL 1.4-dioxane to the product after column chromatography concentration, dissolve it, then add 173mL hydrochloric acid dioxane (4N) and stir for 1h, filter after solid precipitation, wash with dioxane, and dry to obtain 120g of the compound shown in formula (IV), with a yield of 97%. In this embodiment, the molar ratio of the compound shown in formula (III), 1-chloroethyl chloroformate, and hydrochloric acid dioxane is 1:2:1.2.

[0044] Example 3

[0045]

[0046] 1) At room temperature, add 100g of the compound represented by formula (I) to 1L THF, then add 294mL 37% formaldehyde solution and 732mL 40% HBr respectively, stir at room temperature for 20h, detect the reaction by TLC, then heat the mixture to 65℃ and stir for 1h, and then cool to 0℃. Collect the precipitated solid by filtration, wash with cooled HOAc, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 198g of the compound represented by formula (V), with a yield of 84.5%. In this embodiment, the molar ratio of the compound represented by formula (I), 40% HBr, and concentrated hydrochloric acid is 1:5:5.

[0047] 2) Dissolve 198g of the compound represented by formula (V) in 1.98L DMF, add 168g of p-methoxybenzylamine, 46g of potassium iodide and 128g of sodium bicarbonate, react at 40°C for 5h, detect the reaction by TLC, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 167g of the compound represented by formula (III), with a yield of 91%. In this embodiment, the molar ratio of the compound represented by formula (V), p-methoxybenzylamine, potassium iodide and sodium bicarbonate is 1:2:0.2:2.5.

[0048] 3) Dissolve 167g of the compound shown in formula (III) in 1.67L MeOH / DCM mixed solution, keep it at 0℃, slowly add 95g 1-chloroethyl chloroformate, and then heat the mixture under reflux for 3h. The reaction is complete when detected by TLC. Extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, add 833mL 1.4-dioxane to the product after column chromatography concentration, dissolve it, then add 167mL hydrochloric acid dioxane (4N) and stir for 1h, filter after solid precipitation, wash with dioxane, and dry to obtain 114g of the compound shown in formula (IV), with a yield of 96%. In this embodiment, the molar ratio of the compound shown in formula (III), 1-chloroethyl chloroformate, and hydrochloric acid dioxane is 1:1.2:2.

[0049] Example 4

[0050]

[0051] 1) At room temperature, add 100g of the compound represented by formula (I) to 1L THF, then add 176mL 37% formaldehyde solution and 181mL concentrated hydrochloric acid (12N) respectively, stir at room temperature for 20h, and detect the reaction by TLC. Then heat the mixture to 65℃ and stir for 1h, and then cool to 0℃. Collect the precipitated solid by filtration, wash with cooled HOAc, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 138g of the compound represented by formula (II), with a yield of 81%. In this embodiment, the molar ratio of the compound represented by formula (I), 37% formaldehyde solution, and concentrated hydrochloric acid is 1:3:3.

[0052] 2) Dissolve 138g of the compound represented by formula (II) in 1.38L DMF, add 126g of benzylamine, 44g of potassium iodide and 123g of sodium bicarbonate, react at 40°C for 5h, detect the reaction by TLC, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, column chromatography, and obtain 150g of the compound represented by formula (VI), with a yield of 95%. In this embodiment, the molar ratio of the compound represented by formula (III), benzylamine, potassium iodide and sodium bicarbonate is 1:2:0.5:2.5.

[0053] 3) Dissolve 150g of the compound shown in formula (VI) in 1.5L MeOH / DCM mixed solution, keep it at 0℃, slowly add 159g 1-chloroethyl chloroformate, and then heat the mixture under reflux for 3h. The reaction is complete when detected by TLC. Extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, add 750mL 1.4-dioxane to the product after column chromatography concentration, dissolve it, then add 278mL hydrochloric acid dioxane (4N) and stir for 1h, filter after solid precipitation, wash with dioxane, and dry to obtain 116g of the compound shown in formula (IV), with a yield of 96.5%. In this embodiment, the molar ratio of the compound shown in formula (VI), 1-chloroethyl chloroformate, and hydrochloric acid dioxane is 1:2:2.

[0054] Example 5

[0055]

[0056] 1) At room temperature, add 100g of the compound represented by formula (I) to 1L THF, then add 176mL 37% formaldehyde solution and 439mL HBr respectively, stir at room temperature for 20h, and detect the reaction to be complete by TLC, then heat the mixture to 65℃ and stir for 1h, and then cool to 0℃. Collect the precipitated solid by filtration, wash with cooled HOAc, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain 198g of the compound represented by formula (V), with a yield of 84.5%. In this embodiment, the molar ratio of the compound represented by formula (I), 37% formaldehyde solution, and HBr is 1:3:3.

[0057] 2) Dissolve 198g of the compound represented by formula (V) in 1.98L DMF, add 131g benzylamine, 46g potassium iodide and 128g sodium bicarbonate, react at 40°C for 5h, detect the reaction completely by TLC, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, column chromatography, and obtain 150g of the compound represented by formula (VI), with a yield of 91%. In this embodiment, the molar ratio of the compound represented by formula (V), benzylamine, potassium iodide and sodium bicarbonate is 1:2:0.5:2.5.

[0058] 3) Dissolve 150g of the compound represented by formula (VI) in 1.5L DCM, keep it at 0℃, slowly drop 95g of 1-chloroethyl chloroformate, and then heat the mixture under reflux for 3h. The reaction is complete when detected by TLC. Extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, add 750mL 1.4-dioxane to the product after column chromatography concentration, dissolve it, then drop 167mL dioxane hydrochloride (4N) and stir for 1h, filter after solid precipitation, wash with dioxane, and dry to obtain 110g of the compound represented by formula (IV), with a yield of 92%. In this embodiment, the molar ratio of the compound represented by formula (VI), 1-chloroethyl chloroformate, and dioxane hydrochloride is 1:1.2:1.2, and the solvent DCM is a single solvent.

[0059] Effect Example

[0060] Take the 5,6-dimethoxyisoindoline hydrochloride prepared in Examples 1 to 5 and perform nuclear magnetic resonance analysis. The obtained nuclear magnetic resonance 1HNMR spectrum is as follows: Figure 1 As shown. Figure 1 It can be seen that the present invention successfully prepared the target product 5,6-dimethoxyisoindoline hydrochloride.

[0061] The yield and purity (purity test using gas chromatography) of 5,6-dimethoxyisoindoline hydrochloride prepared in Examples 1 to 5 were analyzed. The results are shown in Table 1. The GC spectrum of the 5,6-dimethoxyisoindoline hydrochloride product prepared in Example 1 is shown in Table 1. Figure 2 shown.

[0062] Table 1

[0063]

[0064] Depend on Figure 2 As can be seen from the data in Table 1, the preparation method of 5,6-dimethoxyisoindoline hydrochloride provided by the present invention comprises the following steps: step 1) the compound shown in formula (I) is subjected to Friedel-Crafts acylation of formaldehyde under the conditions of a reaction solvent, and a dihalide is produced in the presence of a hydrogen halide solution to obtain a compound shown in formula (II); step 2) the compound shown in formula (II) is reacted with an amine reagent, potassium iodide and a base under the conditions of a reaction solvent to obtain a compound shown in formula (III); step 3) the compound shown in formula (III) is debenzylated by reacting with 1-chloroethyl chloroformate under the conditions of a reaction solvent to obtain a compound shown in formula (IV). The present invention has the advantages of a simple synthesis route, a controllable reaction process, and reduced generation of by-products and difficulty of subsequent purification. By precisely controlling the reaction conditions and molar ratio, the yield and purity of the target product are significantly improved; the raw materials used in the process are cheap, and no expensive palladium catalyst is used, which significantly reduces the cost and is suitable for the needs of large-scale industrial production.

[0065] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 5,6-dimethoxyisoindoline hydrochloride, the method comprising compound formula (I), compound formula (II), compound formula (III), and compound formula (IV); the specific synthesis route is as follows: Step 1) The compound represented by formula (I) is subjected to Friedel-Crafts acylation of formaldehyde in a reaction solvent to generate a dihalide in the presence of a hydrogen halide solution to obtain a compound represented by formula (II); Step 2) the compound represented by formula (II) reacts with an amine reagent, potassium iodide and a base in a reaction solvent to obtain a compound represented by formula (III); Step 3) The compound represented by formula (III) is debenzylated by reacting with 1-chloroethyl chloroformate in a reaction solvent to obtain a compound represented by formula (IV).

2. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 1), the molar ratio of the formaldehyde to the compound represented by formula (I) is 3-5:

1.

3. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 1), the hydrogen halide is selected from any one of HCl and HBr; the molar ratio of the hydrogen halide to the compound represented by formula (I) is 3-5:

1.

4. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 2), the amine reagent is selected from any one of p-methoxybenzylamine and benzylamine; the molar ratio of the amine reagent to the compound represented by formula (II) is (1.2-2):

1.

5. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 2), the molar ratio of KI to the compound represented by formula (II) is (0.1-0.5):

1.

6. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 2), the base is selected from any one of sodium bicarbonate and sodium tert-butoxide; the molar ratio of the base to the compound represented by formula (II) is (1.5-3):

1.

7. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 3), the molar ratio of 1-chloroethyl chloroformate to the compound represented by formula (III) is (1.2-2):

1.

8. The method for synthesizing 5,6-dimethoxyisoindoline 0.0 hydrochloride according to claim 1, It is characterized in that In step 3), dioxane hydrochloride is also added, and the molar ratio of dioxane hydrochloride to the compound represented by formula (III) is (1.2-2):

1.

9. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 1) to step 2), the reaction solvent is any one of THF and DMF; the ratio of the reaction solvent to the compound represented by formula (I) / formula (II) is (5-20) mL: 1 g.

10. The method for synthesizing 5,6-dimethoxyisoindoline hydrochloride according to claim 1, It is characterized in that In step 3), the reaction solvent is a MeOH / DCM mixed solution, and the volume ratio of MeOH to DCM in the mixed solution is (1-10):1.

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