Method for synthesizing 5-cyanophthalide

Abstract

The present invention relates to a method for synthesizing 5-cyanophthalide. This method utilizes solid phosgene (triphosgene) instead of the thionyl chloride used in the prior art chlorination of 5-carboxyphthalide and the thionyl chloride used in the dehydration of 5-phthalide carboxamide. This method produces fewer pollutants and achieves a higher yield. Therefore, the method is generally more environmentally friendly and efficient, making it suitable for the industrial production of 5-cyanophthalide.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediate synthesis, and in particular to a method for synthesizing 5-cyanophthalide. Background Art

[0002] Citalopram is an antidepressant with the characteristics of few adverse reactions, high relative selectivity, and low toxicity. The synthesis of citalopram is mostly carried out using 5-cyanophthalide as the starting material.

[0003] 5-Cyanophthalide, chemically known as 1,3-dihydro-1-oxo-5-isobenzofurancarbonitrile, has various industrial synthesis methods. One involves reacting terephthalic acid with paraformaldehyde in the presence of fuming sulfuric acid to produce 5-carboxyphthalide. This 5-carboxyphthalide then reacts with thionyl chloride to produce 5-phthaloyl chloride, which is then reacted with ammonia gas or aqueous ammonia to form 5-phthaloylcarboxamide. Finally, thionyl chloride is used to produce the product, 5-cyanophthalide. This production process requires a large amount of thionyl chloride, producing toxic sulfur dioxide and hydrogen chloride as byproducts, making it both uneconomical and environmentally unfriendly. Furthermore, the yield of 5-phthaloylcarboxamide dehydrated with thionyl chloride is low, at only 80% or even lower (see WO0039112; Synthesis of 5-Cyanophthalide, Wang Jingwei et al., Heilongjiang Medicine, Vol. 22, No. 4, pp. 499-500).

[0004] Therefore, it is necessary to develop more methods for efficiently synthesizing 5-cyanophthalide. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a method for synthesizing 5-cyanophthalide. The method does not use thionyl chloride throughout the process, and can synthesize 5-cyanophthalide more environmentally friendly and efficiently.

[0006] The method for synthesizing 5-cyanophthalide of the present invention comprises:

[0007]

[0008] 5-phthalide carboxamide is added to an organic solvent, triphosgene is added, and then a catalyst is added, and the mixture is reacted at 40-90° C. to obtain 5-cyanophthalide, wherein the catalyst is a mixture of N,N-dimethylformamide and 4-dimethylaminopyridine.

[0009] In one embodiment, the organic solvent is selected from at least one of toluene, xylene, ethylbenzene and benzene; preferably, the organic solvent is toluene.

[0010] In one embodiment, triphosgene is dissolved in an organic solvent and then added to the reaction system.

[0011] In one embodiment, the molar ratio of 5-phthalidecarboxamide to triphosgene is 1:0.34-1.5.

[0012] Preferably, the molar ratio of 5-phthalide carboxamide to triphosgene is 1:0.35-1.

[0013] More preferably, the molar ratio of 5-phthalidecarboxamide to triphosgene is 1:0.4-0.6.

[0014] In one embodiment, the mass volume ratio of 5-phthalide carboxamide to the organic solvent in the reaction system is 1 g:3-10 ml, preferably 1 g:4-7 ml.

[0015] In one embodiment, the weight ratio of N,N-dimethylformamide to 4-dimethylaminopyridine is 1:1-5.

[0016] Preferably, the weight ratio of N,N-dimethylformamide to 4-dimethylaminopyridine is 1:1-3.

[0017] More preferably, the weight ratio of N,N-dimethylformamide to 4-dimethylaminopyridine is 1:1 to 2.5.

[0018] In one embodiment, the mass ratio of 5-phthalide carboxamide to the catalyst is 5 to 30:1.

[0019] Preferably, the mass ratio of 5-phthalamide to catalyst is 10 to 25:1.

[0020] More preferably, the mass ratio of 5-phthalamide to catalyst is 15 to 20:1.

[0021] In one embodiment, the reaction temperature is 50 to 85°C, preferably 60 to 80°C.

[0022] In one embodiment, the reaction time is 1 to 24 hours, preferably 4 to 12 hours.

[0023] In one embodiment, the method comprises: after the reaction is completed, evaporating a portion of the organic solvent, then precipitating 5-cyanophthalide, filtering, washing, and then recrystallizing to obtain 5-cyanophthalide.

[0024] Preferably, 20 to 50% of the organic solvent of the total volume of the reaction system is evaporated, and more preferably, 30 to 40% of the organic solvent of the total volume of the reaction system is evaporated.

[0025] Preferably, the mixture is naturally cooled to 20-40° C. to precipitate 5-cyanophthalide, and more preferably cooled to room temperature.

[0026] Preferably, the solvent during recrystallization is selected from at least one of toluene and glacial acetic acid.

[0027] In one embodiment, the method further comprises:

[0028]

[0029] 5-Carboxyphthalide and triphosgene are added to an acyl chloride organic solvent, an acyl chloride catalyst is added, and the temperature is raised to react, so that 5-carboxyphthalide is chlorinated to obtain 5-phthaloyl chloride; then, 5-phthaloyl chloride is reacted with ammonia gas or ammonia water to obtain 5-phthaloyl carboxamide.

[0030] Preferably, the molar ratio of 5-carboxyphthalide to triphosgene is 1:0.34-1.5, preferably 1:0.35-1, and more preferably 1:0.4-0.6.

[0031] Preferably, the acyl chloride organic solvent is selected from at least one of toluene, xylene, ethylbenzene and benzene; preferably, the acyl chloride organic solvent is toluene.

[0032] Preferably, the acyl chloride catalyst is selected from at least one of N,N-dimethylformamide, triethylamine, and pyridine.

[0033] Preferably, the method further comprises adding an anti-solvent after the acyl chlorination reaction to precipitate a solid, filtering, washing, and drying to obtain 5-phthaloyl chloride.

[0034] Preferably, the anti-solvent is at least one of n-hexane, cyclohexane and n-heptane.

[0035] In one embodiment, the method further comprises:

[0036]

[0037] Terephthalic acid is reacted with paraformaldehyde in the presence of concentrated sulfuric acid or fuming sulfuric acid to produce 5-carboxyphthalide.

[0038] Beneficial Effects of the Invention: The present invention provides a method for synthesizing 5-cyanophthalide. This method utilizes solid phosgene (triphosgene) rather than thionyl chloride (which generates more toxic gases) during the dehydration of 5-phthalide carboxamide, resulting in fewer pollutants. However, the dehydration of 5-phthalide carboxamide using triphosgene and conventional catalysts such as pyridine and DMF results in poor reaction efficiency and low product yield. Therefore, the present invention utilizes a specific catalyst combination of DMF and DMAP, enabling high-yield dehydration of 5-phthalide carboxamide to 5-cyanophthalide using triphosgene. This step provides high yield and product purity. Furthermore, the method utilizes triphosgene instead of thionyl chloride during the acylchlorination of 5-carboxyphthalide, further reducing pollutant generation and achieving a higher acylchlorination yield. Therefore, the synthesis method of the present invention is generally more environmentally friendly and efficient, making it suitable for industrial production of 5-cyanophthalide. DETAILED DESCRIPTION

[0039] The present invention is described in more detail below to facilitate understanding of the present invention.

[0040] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0041] Example 1:

[0042] 1) Preparation of 5-carboxyphthalide

[0043] 1L of 25% fuming sulfuric acid, 2.0mol (332g) of terephthalic acid and 3.0mol (90g) of paraformaldehyde were added to a reactor, and the temperature was raised to 135-145°C with stirring and the reaction was carried out for 2.5h. After the reaction was completed, the mixture was cooled to room temperature and poured into 6L of cold water. The pH value was adjusted to 8-9 with 20% sodium hydroxide solution. After adding 10g of activated carbon, the mixture was heated to 60°C, stirred for 0.5h and filtered. The pH value of the filtrate was adjusted to 1-2 with 25% hydrochloric acid. The precipitated solid was filtered, the filter cake was washed with cold water, and dried under reduced pressure to obtain 311g of 5-carboxyphthalide.

[0044] 2) Preparation of 5-phthaloyl chloride

[0045] Take 1.0 mol (178 g) of 5-carboxyphthalide and suspend it in a solution of 0.4 mol (119 g) of triphosgene dissolved in 800 mL of toluene, add 5 g of N, N-dimethylformamide (DMF), heat under reflux for 3 h with stirring, cool to room temperature, add 600 mL of n-heptane and collect the precipitated crystals, wash with n-heptane and dry to obtain 196 g of 5-phthaloyl chloride.

[0046] 3) Preparation of 5-phthalamide

[0047] The 5-phthaloyl chloride prepared in the previous step was dissolved in 600 ml of tetrahydrofuran and added to a solution prepared by 400 ml of 25% ammonia water (5.3 mol) and 500 ml of ice water. The mixture was stirred for 30 min, and the precipitate was collected, filtered, washed with water, and dried to obtain 175 g of 5-phthaloylcarboxamide.

[0048] 4) Preparation of 5-cyanophthalide

[0049] The dried 5-phthalide carboxamide prepared in the previous step was suspended in 500 ml of toluene, and a solution of 0.4 mol of triphosgene dissolved in 500 ml of toluene was added. 5 g of DMF and 5 g of 4-dimethylaminopyridine (DMAP) were added, and the mixture was heated to 75°C for 6 h. About 1 / 3 of the toluene was evaporated, and the remaining solution was cooled to room temperature. The precipitated crystals were filtered and washed with toluene and water respectively. The resulting crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 147.6 g of white flaky 5-cyanophthalide. The yield based on 5-carboxyphthalide was 92.8%, HPLC purity was 99.2%, and ESI-MS: 160.1 [M+H] + , mp.201~203℃ (literature value: 202℃, Tirouflet, Jean; Bull.soc sci.Bretagne Spec.,(1951),No.26,35-43).

[0050] Example 2:

[0051] Take 0.5 mol (89 g) of dried 5-phthalide carboxamide and suspend it in 250 ml of toluene. Add 0.2 mol (59 g) of triphosgene dissolved in 250 ml of toluene, add 1.5 g of DMF and 3.5 g of DMAP, heat to 75 ° C and keep warm for 8 h. Distill about 1 / 3 of toluene, cool the remaining solution to room temperature, filter the precipitated crystals, wash with toluene and water respectively, recrystallize the obtained crystals with toluene, filter and dry under reduced pressure to obtain 75.8 g of 5-cyanophthalide, with a yield of 95.4% and HPLC purity of 99.1%.

[0052] Example 3:

[0053] 0.5 mol (89 g) of dried 5-phthalide carboxamide was suspended in 250 ml of toluene, 0.2 mol (59 g) of triphosgene dissolved in 250 ml of toluene was added, 2 g of DMF and 3 g of DMAP were added, and the mixture was heated to 75 ° C for 7 h. About 1 / 3 of the toluene was evaporated, and the remaining solution was cooled to room temperature. The precipitated crystals were filtered and washed with toluene and water respectively. The resulting crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 73.5 g of 5-cyanophthalide with a yield of 92.5% and an HPLC purity of 98.9%.

[0054] Comparative Example 1:

[0055] 0.5 mol (89 g) of dried 5-phthalide carboxamide was suspended in 250 ml of toluene, and a solution of 0.2 mol (59 g) of triphosgene dissolved in 250 ml of toluene was added. 5 g of DMF was added, and the mixture was heated to 75°C for 6 h. About 1 / 3 of the toluene was evaporated, and the remaining solution was cooled to room temperature. The precipitated crystals were filtered and washed with toluene and water respectively. The resulting crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 66.8 g of 5-cyanophthalide with a yield of 84.1% and an HPLC purity of 98.3%.

[0056] Comparative Example 2:

[0057] 0.5 mol (89 g) of dried 5-phthalide carboxamide was suspended in 250 ml of toluene, and a solution of 0.2 mol (59 g) of triphosgene dissolved in 250 ml of toluene was added. 5 g of pyridine was added, and the mixture was heated to 75°C for 8 h. About 1 / 3 of the toluene was evaporated, and the remaining solution was cooled to room temperature. The precipitated crystals were filtered and washed with toluene and water respectively. The resulting crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 62.2 g of 5-cyanophthalide with a yield of 78.2% and an HPLC purity of 97.9%.

[0058] Comparative Example 3:

[0059] 0.5 mol (89 g) of dried 5-phthalide carboxamide was suspended in 250 ml of toluene, and a solution of 0.2 mol (59 g) of triphosgene dissolved in 250 ml of toluene was added. 5 g of DMAP was added, and the mixture was heated to 75°C for 8 h. About 1 / 3 of the toluene was evaporated, and the remaining solution was cooled to room temperature. The precipitated crystals were filtered and washed with toluene and water respectively. The resulting crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 59.3 g of 5-cyanophthalide with a yield of 74.6% and an HPLC purity of 98.0%.

[0060] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 5-cyanophthalide, comprising: 5-phthalide carboxamide is added to an organic solvent, triphosgene is added, and then a catalyst is added, and the mixture is reacted at 40-90° C. to obtain 5-cyanophthalide, wherein the catalyst is a mixture of N,N-dimethylformamide and 4-dimethylaminopyridine.

2. The method according to claim 1, characterized in that The molar ratio of 5-phthalide carboxamide to triphosgene is 1:0.34-1.

5.

3. The method according to claim 1, characterized in that The weight ratio of N,N-dimethylformamide to 4-dimethylaminopyridine is 1:1-5.

4. The method according to claim 3, characterized in that The weight ratio of N,N-dimethylformamide to 4-dimethylaminopyridine is 1:1-3.

5. The method according to claim 1, wherein The mass ratio of 5-phthalide carboxamide to the catalyst is 5 to 30:

1.

6. The method according to claim 1, characterized in that The method comprises the following steps: after the reaction is completed, a portion of the organic solvent is evaporated, 5-cyanophthalide is precipitated, and the 5-cyanophthalide is filtered, washed, and then recrystallized to obtain the 5-cyanophthalide.

7. The method according to claim 1, characterized in that The method further comprises: 5-Carboxyphthalide and triphosgene are added to an acyl chloride organic solvent, an acyl chloride catalyst is added, and the temperature is raised to react, so that 5-carboxyphthalide is chlorinated to obtain 5-phthaloyl chloride; then, 5-phthaloyl chloride is reacted with ammonia gas or ammonia water to obtain 5-phthaloyl carboxamide.

8. The method according to claim 7, characterized in that The acyl chloride catalyst is selected from at least one of triethylamine and pyridine.

9. The method according to claim 7, characterized in that The method further comprises adding an anti-solvent after the acyl chlorination reaction is completed to precipitate a solid, filtering, washing, and drying to obtain 5-phthaloyl chloride.

10. The method according to claim 7, characterized in that The method further comprises: Terephthalic acid is reacted with paraformaldehyde in the presence of concentrated sulfuric acid or fuming sulfuric acid to produce 5-carboxyphthalide.

Images