Method for synthesizing 5-cyanophthalide

Abstract

The invention relates to a method for synthesizing 5-cyanophthalide. According to the method, the triphosgene triphosgene is adopted to replace thionyl chloride used in 5-carboxyphthalide acylating chlorination and thionyl chloride used in 5-phthalide formamide dehydration in the prior art, few pollutants are generated, and the yield of the synthesis method is higher. Therefore, the synthetic method disclosed by the invention is more environment-friendly and efficient on the whole, and is suitable for 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, low toxicity, etc. The synthesis of Citalopram is mostly carried out with 5-cyanophthalide as the starting material.

[0003] The chemical name of 5-cyanophthalide is 1,3-dihydro-1-oxy-5-isobenzofurancarbonitrile. There are many industrial synthesis methods. One of the methods is to use terephthalic acid to react with polyformaldehyde under the action of fuming sulfuric acid to first generate 5-carboxyphthalide, and then 5-carboxyphthalide reacts with thionyl chloride to generate 5-phthaloyl chloride, and then reacts with ammonia gas or ammonia water to generate 5-phthaloyl carboxamide, and finally generates the product 5-cyanophthalide under the action of thionyl chloride. A large amount of thionyl chloride is used in the whole production process, and toxic gases such as sulfur dioxide and hydrogen chloride are produced as by-products. The production is not economical and extremely environmentally unfriendly; in addition, the yield of 5-phthaloyl carboxamide dehydrated by thionyl chloride is not high, only 80% or even lower (see WO0039112; Synthesis of 5-cyanophthalide, Wang Jingwei et al., Heilongjiang Medicine, Vol. 22, No. 4, 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, wherein the method does not use thionyl chloride throughout the whole process and can synthesize 5-cyanophthalide in a more environmentally friendly and efficient manner.

[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-phthalide carboxamide 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-phthalide carboxamide to triphosgene is 1:0.4 to 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 to 10 ml, preferably 1 g: 4 to 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 the catalyst is 10 to 25:1.

[0020] More preferably, the mass ratio of 5-phthalamide to the 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, part of the organic solvent is evaporated, and then 5-cyanophthalide is precipitated, filtered, washed and then recrystallized 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 acyl chlorided 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 is completed 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 generate 5-carboxyphthalide.

[0038] Beneficial effects of the present invention: The present invention provides a method for synthesizing 5-cyanophthalide. The method does not use thionyl chloride that will generate more toxic gases in the dehydration of 5-phthalide carboxamide, but uses solid phosgene triphosgene, which produces fewer pollutants; however, when 5-phthalide carboxamide uses triphosgene and conventional catalysts such as pyridine and DMF during dehydration, the reaction effect is not reasonable and the product yield is not high. For this reason, the present invention uses a specific catalyst combination of DMF and DMAP, so that when triphosgene is used, 5-phthalide carboxamide can be dehydrated and converted into 5-cyanophthalide with a high yield, and the yield of this step is high and the product purity is also high. In addition, the method of the present invention also uses triphosgene instead of thionyl chloride in the process of acyl chlorination of 5-carboxyphthalide, which further reduces the generation of pollutants and obtains a higher acyl chlorination yield. Therefore, the synthesis method of the present invention is generally more environmentally friendly and efficient, and is suitable for industrial production of 5-cyanophthalide. DETAILED DESCRIPTION

[0039] The present invention is described in more detail hereinafter 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 are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0041] Embodiment 1:

[0042] 1) Preparation of 5-carboxyphthalide

[0043] Add 1L of 25% fuming sulfuric acid, 2.0mol (332g) of terephthalic acid and 3.0mol (90g) of polyformaldehyde into a reactor, heat to 135-145°C with stirring and keep warm for reaction for 2.5h; after the reaction is completed, cool to room temperature, pour it into 6L of cold water, adjust the pH value to 8-9 with 20% sodium hydroxide solution, add 10g of activated carbon and heat to 60°C, keep warm and stir for 0.5h and then filter, adjust the pH value of the filtrate to 1-2 with 25% hydrochloric acid, filter the precipitated solid, wash the filter cake with cold water, and dry 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, added to a solution prepared by 400 ml of 25% ammonia water (5.3 mol) and 500 ml of ice water, stirred for 30 min, 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 obtained 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, and 5 g of DMF and 5 g of 4-dimethylaminopyridine (DMAP) were added, and the mixture was heated to 75°C for 6 h, and about 1 / 3 of toluene was evaporated. The remaining solution was cooled to room temperature, and the precipitated crystals were filtered, washed with toluene and water respectively, and the obtained crystals were recrystallized from toluene, filtered, and dried under reduced pressure to obtain 147.6 g of white flaky 5-cyanophthalide, with a yield of 92.8% based on 5-carboxyphthalide, HPLC purity, 99.2%, 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] Embodiment 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 for 8 hours, evaporate 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] Embodiment 3:

[0053] 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 2 g of DMF and 3 g of DMAP, heat to 75 ° C for 7 hours, evaporate 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 73.5 g of 5-cyanophthalide, with a yield of 92.5% and 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, 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 obtained 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 a 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, and 5 g of pyridine was added. The mixture was heated to 75°C and kept warm 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 obtained 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 a 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, 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 obtained 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 a 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, characterized in that The mass ratio of 5-phthalamide 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 part of the organic solvent is evaporated, 5-cyanophthalide is precipitated, and then 5-cyanophthalide is filtered, washed and recrystallized to obtain 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 acyl chlorided 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 generate 5-carboxyphthalide.

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