CN1962651A - Preparation process of key intermediate 5-cyanphthalide of antidepressant drug citalopram - Google Patents

Abstract

The invention discloses a preparation process of the key intermediate 5-cyanophthalide of the antidepressant citalopram. It uses alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N, N'-dimethylethylenediamine as the combined catalyst, 5-bromophthalide and sodium cyanide under the protection of nitrogen at 100-150 React at ℃ for 20-48 hours, then recover the solvent under reduced pressure, then add water, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain the molar equivalents of 5-cyanophthalide, 5-bromophthalide and sodium cyanide The ratio is 1:1.0~2.0; the dosage of cuprous iodide is 5~30% molar equivalent of 5-bromophthalide, the dosage of potassium iodide is 1.5~3 molar equivalent of cuprous iodide; N,N'-dimethyl The consumption of ethylenediamine is 1～1.5 molar equivalents of 5-bromophthalide. The invention has the following advantages: 1) mild reaction conditions; 2) short reaction process flow; 3) use of cheap reagents; 4) very simple feeding and post-treatment, easy to realize large-scale industrial production.

Description

Preparation process of key intermediate 5-cyanophthalide of antidepressant citalopram

technical field

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation process of a key intermediate of citalopram, an antidepressant, 5-cyanophthalide.

Background technique

The chemical name of 5-cyanophthalide (5-Cyano-phthalide) is 1,3-dihydro-1-oxo-5-isobenzofuranonitrile, which is the key intermediate for the synthesis of antidepressant citalopram. body. Therefore, how to efficiently synthesize 5-cyanophthalide has attracted great attention. The synthesis of 5-cyanophthalide has been reported in some literatures. For example, the document WO00112044, 2000-03-09 reported that 5-carboxyphthalide was prepared by using phthalic acid and paraformaldehyde as starting materials under the action of oleum. It can be prepared by thionyl chloride chlorination, amidation of ammonia and dehydration of sulfolane. Literature "Chemical and Biological Engineering" 2006, Vo1.23, No.6, 17-18 and "Chinese Journal of Pharmaceutical Industry" 2004, 35(6), 330-331, etc. use phthalimide as the starting material After nitration, reduction, cyclization and Sandmeyer cyanation reaction, 5-cyanophthalide was synthesized. Document CN1379025 reports to be starting raw material with 5-carboxyphthalide, reacts with inorganic ammonia or inorganic ammonium salt or small molecular weight organic acid ammonium salt to obtain corresponding 5-phthalide ammonium formate, 5-phthalide ammonium formate, in solvent In the presence of a catalyst, 5-cyanophthalide can be obtained through the dehydration reaction of a dehydrating agent. Document CN1331686 reports that 5-carboxy 2-benzo[c]furanone is converted into the corresponding amide, and then reacted with a dehydrating agent to obtain 5-cyanophthalide. The reaction process of the above-mentioned synthetic processes has a long cycle time and harsh conditions, or many experimental processes involve strong acid or strong alkali conditions, low yield, complicated post-treatment and other problems. Therefore, under mild conditions, it is very important and urgent to efficiently solve the synthesis of 5-cyanophthalide.

Contents of the invention

The object of the present invention is to provide a kind of preparation technology of antidepressant citalopram key intermediate 5-cyanophthalide.

It uses alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N, N'-dimethylethylenediamine as the combined catalyst, 5-bromophthalide and sodium cyanide under the protection of nitrogen at 100 to 150 ℃ for 20 to 48 hours, then recover the solvent under reduced pressure, then add water, filter, wash with water, and finally recrystallize the filtrate with ethanol to obtain the molar equivalents of 5-cyanophthalide, 5-bromophthalide and sodium cyanide The ratio is 1:1.0～2.0; the consumption of cuprous iodide is 5～30% molar equivalent of 5-bromophthalide, the consumption of potassium iodide is 1.5～3 molar equivalent of cuprous iodide; N, N'-dimethyl The consumption of ethylenediamine is 1～1.5 molar equivalents of 5-bromophthalide, and the reaction formula is:

The reaction solvent alkylbenzene is toluene, ethylbenzene or xylene. The reaction time is preferably 20 to 36 hours. The reaction temperature is preferably 100 to 130°C. The molar equivalent ratio of 5-bromophthalide and sodium cyanide is preferably 1: 1.0～1.5; The consumption of cuprous iodide is 5～20% molar equivalent of 5-bromophthalide; The consumption of potassium iodide is preferably cuprous iodide 1.5-2.5 molar equivalents of N, N'-dimethylethylenediamine is preferably 1-1.2 molar equivalents of 5-bromophthalide.

Compared with existing synthetic methods, the present invention has the following advantages:

1) mild reaction conditions;

2) The reaction process flow is short;

3) Use cheap reagents;

4) Feeding and post-processing are very simple, and it is easy to realize industrialized large-scale production.

Detailed ways

The molecular formula of 5-cyanophthalide is:

The specific reaction steps of the preparation technology of antidepressant citalopram key intermediate 5-cyanophthalide are as follows:

With alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N,N'-dimethylethylenediamine as the combined catalyst, 5-bromophthalide and sodium cyanide react at 100-150°C under nitrogen protection After 20 to 48 hours, the solvent is recovered under reduced pressure, then water is added, filtered, washed with water, and finally the filtrate is recrystallized with ethanol and separated to obtain 5-cyanophthalide with high yield and high purity. Wherein the molar equivalent ratio of 5-bromophthalide and sodium cyanide is 1: 1.0～2.0; The consumption of cuprous iodide is 5～30% molar equivalent of 5-bromophthalide; The consumption of potassium iodide is the amount of cuprous iodide 1.5-3 molar equivalents; the amount of N,N'-dimethylethylenediamine is 1-1.5 molar equivalents of 5-bromophthalide. The recommended reaction solvent alkylbenzene is toluene, ethylbenzene, xylene, and toluene is the most preferred. The recommended response time is 20 to 36 hours, with 24 hours being the most preferred. The recommended reaction temperature is 100-130°C, most preferably 110°C. It is recommended that the molar equivalent ratio of 5-bromophthalide and sodium cyanide is 1:1.0~1.5, the most preferred is 1:1.2; the amount of cuprous iodide is 5-20% molar equivalent of 5-bromophthalide, the most preferred 10% molar equivalent; the dosage of potassium iodide is 1.5-2.5 molar equivalents of cuprous iodide, the most preferred is 2 molar equivalents; the dosage of N,N'-dimethylethylenediamine is 1-1.2 molar equivalents of 5-bromophthalide Molar equivalent, most preferably 1 molar equivalent. The following examples will help to understand the present invention, but are not limited to the content of the present invention:

Example 1

In a 100 ml three-necked flask, 50 ml of toluene, 6.4 g (30 mmol) of 5-bromophthalide, 1.18 g (36 mmol, 1.2 equivalents) of sodium cyanide, 0.573 g (3 mmol) of sodium cyanide were added successively under nitrogen protection. , 0.1 equivalent) cuprous iodide, 1 gram of potassium iodide (6 mmol, 0.2 equivalent), 2.64 grams of N, N'-dimethylethylenediamine (30 mmol, 1.0 equivalent), under nitrogen protection at 110 ° C Stir the reaction for 30 hours, end the reaction, recover the solvent toluene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanobenzene Phthale, the yield is 90%, the purity is 98% (HPLC), and the melting point is 200-202°C. ¹ HNMR (CDCl ₃ , ppm): 5.51 (2H, s), 7.55 (1H, s), 7.55 (1H, s), 8.05 (1H, d, J=2.5Hz).

Example 2

In a 100 ml three-necked flask, 60 ml of ethylbenzene, 6.4 g (30 mmol) of 5-bromophthalide, 1.6 g (39 mmol, 1.3 equivalents) of sodium cyanide, 0.573 g (3 mg) of sodium cyanide were added successively under nitrogen protection. mol, 0.1 equivalent) cuprous iodide, 1 gram of potassium iodide (6 mmol, 0.2 equivalent), 2.64 grams of N, N'-dimethylethylenediamine (30 mmol, 1.0 equivalent), under nitrogen protection at 130 Stir the reaction at ℃ for 24 hours, end the reaction, recover the solvent ethylbenzene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization from ethanol to obtain white needle-shaped crystals of 5-cyanide phenylphthalide, the yield is 85%, the purity is 99%, and the melting point is 201-202°C.

Example 3

In a 100 ml three-necked flask, 50 ml of toluene, 6.4 g (30 mmol) of 5-bromophthalide, 1.18 g (36 mmol, 1.2 equivalents) of sodium cyanide, 0.7 g (4.5 mmol) of sodium cyanide were added successively under nitrogen protection. , 0.15 equivalents) cuprous iodide, 1.5 grams of potassium iodide (9 mmoles, 0.3 equivalents), 2.64 grams of N, N'-dimethylethylenediamine (30 mmoles, 1.0 equivalents), under nitrogen protection at 100 ° C Stir the reaction for 48 hours, end the reaction, recover the solvent toluene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanobenzene Phthale, the yield is 91%, the purity is 98%, and the melting point is 200-202°C.

Example 4

In a 100 ml three-necked flask, 60 ml of xylene, 6.4 g (30 mmol) of 5-bromophthalide, 2.5 g (60 mmol, 2 equivalents) of sodium cyanide, 1.7 g (9 mg) of sodium cyanide were added successively under nitrogen protection. Moles, 0.3 equivalents) cuprous iodide, 2 grams of potassium iodide (12 mmoles, 0.4 equivalents), 3.6 grams of N, N'-dimethylethylenediamine (45 mmoles, 1.5 equivalents), under nitrogen protection at 150 Stir the reaction at ℃ for 20 hours, end the reaction, recover the solvent ethylbenzene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanide phenylphthalide, the yield is 83%, the purity is 99%, and the melting point is 201-202°C.

Example 5

In a 100 ml three-necked flask, 50 ml of toluene, 6.4 g (30 mmol) of 5-bromophthalide, 1.0 g (30 mmol, 1.0 equivalent) of sodium cyanide, 0.7 g (4.5 mmol) of sodium cyanide were added successively under nitrogen protection. , 0.15 equivalents) cuprous iodide, 1.5 grams of potassium iodide (9 mmoles, 0.3 equivalents), 2.64 grams of N, N'-dimethylethylenediamine (30 mmoles, 1.0 equivalents), under nitrogen protection at 105 ° C Stir the reaction for 48 hours, end the reaction, recover the solvent toluene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanobenzene Phthalophthalein, the yield is 86%, the purity is 98%, and the melting point is 200-202°C.

Claims (5)

1. A preparation process of antidepressant citalopram key intermediate 5-cyanophthalide, characterized in that it is a reaction solvent with alkylbenzene, cuprous iodide, potassium iodide and N, N'-di Methylethylenediamine is the combined catalyst, 5-bromophthalide and sodium cyanide are reacted at 100-150°C under nitrogen protection for 20-48 hours, then the solvent is recovered under reduced pressure, then water is added, filtered, washed with water, and finally filtered out The material is recrystallized and separated with ethanol to obtain 5-cyanophthalide, and the molar equivalent ratio of 5-bromophthalide and sodium cyanide is 1: 1.0～2.0; the consumption of cuprous iodide is 5～30 of 5-bromophthalide. % molar equivalent, the consumption of potassium iodide is 1.5～3 molar equivalents of cuprous iodide; the consumption of N, N'-dimethylethylenediamine is 1～1.5 molar equivalents of 5-bromophthalide, and the reaction formula is: 2. the preparation technology of a kind of antidepressant citalopram key intermediate 5-cyanophthalide according to claim 1 is characterized in that described reaction solvent alkylbenzene is toluene, ethylbenzene or xylene. 3. the preparation technology of a kind of antidepressant citalopram key intermediate 5-cyanophthalide according to claim 1, it is characterized in that described reaction time is 20～36 hours. 4. the preparation technology of a kind of antidepressant citalopram key intermediate 5-cyanophthalide according to claim 1, it is characterized in that described reaction temperature is 100～130 ℃. 5. the preparation technology of a kind of antidepressant citalopram key intermediate 5-cyanophthalide according to claim 1 is characterized in that the molar equivalent ratio of described 5-bromophthalide and sodium cyanide is 1: 1.0~1.5; the amount of cuprous iodide is 5~20% molar equivalent of 5-bromophthalide; the amount of potassium iodide is 1.5~2.5 molar equivalent of cuprous iodide; The amount of diamine used is 1 to 1.2 molar equivalents of 5-bromophthalide.