CN103360353A - Preparation methods for impurities of escitalopram oxalate - Google Patents

Abstract

。The present invention relates to a brand-new synthesis method for three impurities of escitalopram oxalate, which is of great significance for synthesizing high-purity escitalopram oxalate. The present invention mainly studies citalopram amide impurity 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide (II ), citalopram lactone impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisophenylpropane-5-carbonitrile (III), citalopram-N-oxidized impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisopropylfuran-5-carbonitrile -The synthesis of N-oxide compound (IV), their specific synthetic routes are as follows:

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Description

Preparation method of escitalopram oxalate impurity

technical field

The invention relates to a preparation method of escitalopram oxalate impurity. the

Background technique

Escitalopram Oxalate, chemical name: S-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro Isobenzofuran-5-nitrile oxalate, a serotonin reuptake inhibitor (SSRI), is the S-isomer of citalopram (I) (structural formula below) (trade name Lexapro). Studies have shown that escitalopram oxalate has a unique serotonin isomeric site binding mechanism and is highly selective for serotonin receptors. Jointly developed by Forest Laboratories of the United States and Lundbeck of Denmark, escitalopram oxalate was first launched in Switzerland and other European and American countries in March 2002, and was approved by the FDA in August for use in severe cases. Treatment of depression and maintenance treatment of depression. the

The synthetic main reaction route of escitalopram oxalate and citalopram (I) is as follows:

(1) By reacting 5-cyanophthalide with p-fluorobromobenzene Grignard reagent, and then reacting with N,N-dimethyl-3-chloropropylamine Grignard reagent to form hydrobromide and then free to generate 4- (4-Dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-hydroxymethyl-1-benzonitrile; after purification and resolution, (S)-4-(4-dimethyl Amino-1-p-fluorophenyl-1-hydroxybutyl)-3-hydroxymethyl-1-benzonitrile; and triethylamine, p-toluenesulfonyl chloride ring closure reaction makes (S)-citalopram; Reaction with oxalic acid produces escitalopram oxalate. This route is relatively short, the cost is reasonable, and it is beneficial to industrial production (WO2010004575; US2011092719; US2011065938; U.S. Pat. NO. 4650884; U.S. Pat. NO. 4943590). The synthetic route is shown in the following formula. the

(2) by reacting 5-cyanophthalide with p-fluorobromobenzene Grignard reagent, then reacting with N, N-dimethyl-3-chloropropylamine Grignard reagent, after quenching, into hydrobromide, and then Free to generate 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-hydroxymethyl-1-benzonitrile; finally react with triethylamine and p-toluenesulfonyl chloride Citalopram (I) was prepared (US2010/0087664A1). The process is relatively mature, the cost is relatively low, and the application is relatively wide. the

(3) 4-(4-fluorobenzoyl)-3-hydroxymethyl-1-benzonitrile is produced by the reaction of 5-cyanophthalide and p-fluorobromobenzene Grignard reagent, which is reduced by lithium tetrahydrogen to generate 4-[1-(4-fluorophenyl) hydroxymethyl)]-3-hydroxymethyl-1-benzonitrile, ring closure to generate 1-(4-fluorophenyl)-1,3-dihydroiso Benzofuran-5-carbonitrile was alkylated with N,N-dimethyl-3-chloropropane in the presence of sodium hydride to obtain citalopram (I) (WO2005/077927A1; WO2004080988). This route adopts flammable and dangerous reagents such as lithium aluminum hydride and sodium hydride, which is unfavorable for suitability for industrialized production. the

(4) Use 5-cyanophthalide as raw material, react with p-fluorobromobenzene Grignard reagent, hydrolyze, reduce with sodium borohydride, close ring, and then react with N, N-dimethyl-3-chloropropylamine Grignard reagent The reaction can also produce citalopram (I) (W098/19511)

The key to obtaining high-purity escitalopram oxalate lies in the control of impurities, so the research on the synthesis of escitalopram oxalate impurities is of great significance. The United States Pharmacopoeia USP35-NF30 points out that the total impurities of escitalopram oxalate should not exceed 0.5%, and the six impurities that need to be studied include: citalopram amide impurities, chemical name: 1-[3-(dimethylamino)propyl ]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide; citalopram lactone impurity, chemical name: 1-[3-(dimethylamino)propyl ]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisopropylfuran-5-carbonitrile; citalopram N-oxidized impurity, chemical name: 1-[3-(dimethyl Amino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisopropylfuran-5-carbonitrile N-oxide; citalopram demethylation impurity, chemical name: 1-[3 -(methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile; citalopram acetal impurity, chemical name: 1-[3-( Dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-3H-2-benzofuran-5-carbonitrile; citalopram Grignard reaction impurity, chemical name: 4-(dimethyl amino)-1-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3H-2-benzofuran-5-yl]-1-butanone. There are very few reports on the synthesis of citalopram impurities at home and abroad, especially for citalopram amide impurities (II), citalopram lactone impurities (III) and citalopram N-oxidized impurities (IV) (structural formula is as follows) The synthesis of the three impurities has not been reported in the literature. the

Contents of the invention

The present invention relates to three impurities of escitalopram oxalate: the synthetic method of citalopram amide impurity (II), citalopram lactone impurity (III) and citalopram-N-oxidized impurity (IV), the present invention The synthetic route of is as follows:

The preparation of these three impurities all takes citalopram (I) as raw material. Wherein the preparation of citalopram (I) can adopt prior art, and its synthetic steps are: react by 5-cyanophthalide and p-fluorobromophenyl Grignard reagent, then with N,N-dimethyl-3-chloro Propylamine Grignard reagent reaction, after quenching, into hydrobromide, after free, 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-hydroxymethyl-1- Benzonitrile; Finally, citalopram (I) (US2010/0087664A1) was obtained through a cyclization reaction. the

The preparation methods of the three impurities have not been reported in the literature so far, and belong to a new synthesis method. the

Synthetic steps of the present invention:

(1) Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide (II)

① Citalopram amide impurity (II) is prepared from citalopram (I) by adding hydrogen peroxide under alkaline conditions, and the reaction temperature is -10～10°C. the

2. in the preparation method of citalopram amide impurity (II), solvent used is selected from methanol, ethanol, isopropanol, n-butanol, acetone, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, ethyl acetate, tetrahydropyrrole, Pyridine, piperidine, N-methylpyrrolidone. the

In the preparation method of citalopram amide impurity (II), the weight volume ratio of citalopram (I) and 30% hydrogen peroxide is 1: 0.3～0.6; The weight volume ratio of citalopram (I) and solvent is 1 : 35-45. the

3. add the citalopram amide impurity (II) that hydrogen peroxide makes under alkaline condition, wherein, the kind of described alkali and consumption all can be the conventional solvent and consumption of this type of reaction in this area, the present invention preferably following The consumption of alkali and alkali: wherein, described alkali is preferably sodium hydride, lithium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide, potassium tert-butoxide, Lithium tert-butoxide; the amount of the base is preferably adjusted to a pH of 9-11. the

4. Add the citalopram amide impurity (II) that hydrogen peroxide makes under alkaline condition, extract with the larger mixed solvent of polarity, solvent used is selected from n-butanol, isopropanol, ethanol, methyl alcohol, ethyl acetate, Toluene, acetone, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, the present invention preferably n-butanol/ethyl acetate series solvents. the

5. In the preparation method of citalopram amide impurity (II), the purification of citalopram amide impurity (II) adopts silica gel column chromatography, and the eluent adopts methanol/methylene chloride system, preferably methanol: methylene chloride=1: 2~4. the

(2) Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (III)

1. the preparation method of citalopram lactone impurity (III), citalopram (I) reacts with Jones reagent, and reaction is carried out in aprotic solvent, and used solvent is selected from acetone, acetonitrile, DMF, ethyl acetate, DMSO, Tetrahydrofuran, diethyl ether, isopropyl ether, methylene chloride, chloroform, carbon tetrachloride, toluene, benzene, or xylene. the

2. the preparation method of citalopram lactone impurity (III), in citalopram (I) and Jones reagent reaction, the weight volume ratio of citalopram (I) and solvent is 1: 5～15; Reaction temperature is- 10-10°C. the

③ The preparation method of citalopram lactone impurity (III), in the reaction of citalopram (1) and Jones reagent, the weight to volume ratio of citalopram (I) and Jones reagent is 1: 2～5. the

4. make citalopram lactone impurity (III) and extract with the bigger solvent of polarity, used solvent is selected from Virahol, ethanol, methyl alcohol, n-butanol, ethyl acetate, acetone, THF, dichloromethane, Chloroform, acetonitrile, the present invention preferably isopropanol, ethyl acetate, acetone. the

5. make citalopram lactone impurity (III) into oxalate, use the larger solvent recrystallization of polarity, the used solvent of refining is selected from ethanol, methyl alcohol, Virahol, n-butanol, ethyl acetate, acetone, Tetrahydrofuran, dichloromethane, chloroform, acetonitrile, alcohol series are preferred in the present invention. the

(3) 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisophenylpropane-5-carbonitrile-N-oxide (IV) preparation

1. the preparation method of citalopram-N-oxidized impurity (IV), citalopram (I) and m-chloroperoxybenzoic acid reaction are carried out in aprotic solvent, and solvent used is selected from dichloromethane, acetone, acetonitrile, DMF , ethyl acetate, DMSO, tetrahydrofuran, diethyl ether, isopropyl ether, chloroform, carbon tetrachloride, toluene, benzene or xylene. the

2. the preparation method of citalopram-N-oxidized impurity (IV), the weight volume ratio of citalopram (I) and solvent in citalopram (I) and m-chloroperoxybenzoic acid reaction is 1: 18～25; Reaction The temperature is -10 to 10°C. the

3. the preparation method of citalopram-N-oxidized impurity (IV), the mol ratio of citalopram (I) and m-chloroperbenzoic acid 1: 1.0～ 2.5. the

4. the preparation method of citalopram-N-oxidized impurity (IV), makes citalopram-N-oxidized impurity (IV) and extracts with mixed solvent, and used solvent is selected from n-butanol, Virahol, ethanol, methyl alcohol , ethyl acetate, acetone, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, the present invention's preferred mixed solution of n-butanol and ethyl acetate. the

⑤ The obtained N-oxidized impurity (IV) is purified by silica gel column chromatography, and the eluent is n-butanol/ethyl acetate system. The eluent ratio of silica gel column chromatography is preferably n-butanol:ethyl acetate=1:2-4. the

Detailed ways

The following examples further illustrate the invention, but the invention is not limited thereto. the

Example:

Preparation of Example 11-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide (II)

Add 2.0g of citalopram (I) into a 100ml three-necked bottle, add 80ml of methanol and stir to dissolve at 0-5°C, adjust the pH to 10 with dilute sodium hydroxide solution, add 0.6ml of 30% hydrogen peroxide dropwise , and then added 0.2ml of 30% hydrogen peroxide every 30min until the TCL tracking reaction was complete. Add an appropriate amount of saturated sodium bisulfite solution and stir until the starch potassium iodide test paper does not change color, then adjust the pH to alkaline with dilute aqueous sodium hydroxide solution, extract with n-butanol/ethyl acetate (15ml×3), combine the organic layers, and anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain crude product (II). Silica gel column chromatography (methanol/dichloromethane=1/3) gave 0.9 g of pure white solid (II), with a yield of 42.6%. the

Its structural identification data are as follows:

¹ H-NMR (DMSO-d ₆ ) δ: 7.90(s, 1H), 7.80(d, 1H), 7.75(s, 1H), 7.57(m, 3H), 7.30(s, 1H), 7.13(t , 2H), 5.15(m, 2H), 2.13(m, 4H), 2.02(d, 6H), 1.30(s, 1H), 1.22(s, 1H).

MS (m/z): 343 (M ⁺ ).

Example 2 Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (III)

Add 8.0 g of citalopram and 80 ml of acetone into a 250 ml three-necked bottle, stir and dissolve at 0-5°C, add 30 ml of Jones reagent dropwise, stir for 30 min, and move to room temperature to react overnight. Add an appropriate amount of isopropanol, stir for 30 minutes, filter with diatomaceous earth, adjust the pH of the filtrate to 13 in an ice-water bath, extract with ethyl acetate (20ml×3), combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure. The isopropanol was dissolved, and oxalic acid was added to form a salt, and the isopropanol was recrystallized to obtain 6.0 g of pure light yellow oil (III), with a yield of 75.8%. the

Its structural identification data are as follows:

¹ H-NMR (DMSO-d ₆ ) δ: 8.45(s, 1H), 8.28(d, 1H), 8.08(d, 1H), 7.62(m, 2H), 7.26(t, 2H), 2.93(t , 2H), 2.64(t, 1H), 2.50(d, 6H), 2.40(m, 1H), 1.48(s, 1H), 1.35(s, 1H).

MS (m/z): 339 (M ⁺ ).

Example 3 Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisopropylfuran-5-carbonitrile-N-oxide (IV)

Add 2.34g citalopram base (I) in the 250ml three-necked bottle, dichloromethane 50ml, stirring and dissolving under ice-salt bath condition, add dropwise the dichloromethane solution 50ml that contains m-chloroperoxybenzoic acid 1.72g, dropwise Finished and continued to stir for 2h. The reaction solution was quenched with sodium bisulfite solution, concentrated under reduced pressure, added an appropriate amount of water to the residue, added dilute sodium hydroxide solution to adjust the pH to alkaline, extracted with n-butanol/ethyl acetate (20ml×3), anhydrous sulfuric acid Dry over sodium, concentrate under reduced pressure to obtain the crude product (IV), and perform silica gel column chromatography (n-butanol/ethyl acetate=1/3) to obtain 0.13 g of pure light yellow oil (IV), with a yield of 5.6%. the

Its structural identification data are as follows:

¹ H-NMR (DMSO-d ₆ ) δ: 7.82(m, 3H), 7.62(m, 2H), 7.20(t, 2H), 5.25(m, 2H), 3.60(t, 2H), 3.35(s , 6H), 2.26(t, 2H), 1.67(m, 2H).

MS (m/z): 341 (M ⁺ ).

Claims (10)

1. the preparation method of escitalopram oxalate impurity, it is characterized in that 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile (I) (abbreviation citalopram) is by being hydrolyzed to get 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-methane amide (II) (being called for short the citalopram amide impurities); Citalopram (I) reacts to get 1-[3-(dimethylamino) propyl group with Jones reagent]-1-(4-fluorophenyl)-3-oxygen-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile (III) (being called for short citalopram lactone impurity); Citalopram (I) reacts to get 1-[3-(dimethylamino) propyl group with metachloroperbenzoic acid]-1-(4-fluorophenyl)-1, the different phenylpropyl alcohol furans of 3-dihydro-5-nitrile-N-oxide compound (IV) (being called for short citalopram-N-oxidation impurities).

。

2. the preparation method of citalopram amide impurities according to claim 1 (II), (II) preparation is as raw material take citalopram (I), adding hydrogen peroxide under the alkaline condition makes, temperature of reaction is-10～10 ℃, and the reaction solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, pyridine, piperidines, N-Methyl pyrrolidone.

3. described according to claim 2, add the citalopram amide impurities (II) that hydrogen peroxide makes under the alkaline condition, alkaline condition needs highly basic control pH value of solution: scope 9～11; Citalopram (I) is 1: 0.3～0.6 with the weightmeasurement ratio of 30% hydrogen peroxide; Citalopram (I) is 1: 35～45 with the weightmeasurement ratio of solvent.

4. according to claim 2,3 is described, among the preparation method of citalopram amide impurities (II), the citalopram amide impurities (II) that makes is extracted with the larger mixed solvent of polarity, and solvent for use is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, toluene, acetone, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF); Refining silica gel column chromatography method (the eluent employing methyl alcohol: methylene dichloride=1: 2～4) that adopts of citalopram amide impurities (II).

5. the preparation method of citalopram lactone impurity according to claim 1 (III), citalopram (I) and Jones reagent reaction, reaction is carried out in non-protonic solvent, and solvent for use is selected from acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene; Reaction citalopram (I) is 1: 5～15 with the weightmeasurement ratio of solvent; Temperature of reaction is-10～10 ℃.

6. the preparation method of citalopram lactone impurity according to claim 1 (III), during citalopram (I) reacts with Jones reagent, citalopram (I) is 1: 2～5 with the weightmeasurement ratio of Jones reagent, make citalopram lactone impurity (III) with the larger solvent extraction of polarity, used solvent is selected from Virahol, ethanol, methyl alcohol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile.

7. according to claim 1, the 6 described citalopram lactone impurity (III) that make become oxalate, with the larger solvent recrystallization of polarity, refining used solvent is selected from ethanol, methyl alcohol, Virahol, propyl carbinol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, preferred alcohols series of the present invention.

8. the preparation method of citalopram according to claim 1-N-oxidation impurities (IV), citalopram (I) carries out in non-protonic solvent with the metachloroperbenzoic acid reaction, and solvent for use is selected from methylene dichloride, acetone, acetonitrile, DMF, ethyl acetate, DMSO, tetrahydrofuran (THF), ether, isopropyl ether, chloroform, tetracol phenixin, toluene, benzene or dimethylbenzene; Reaction citalopram (I) is 1: 18～25 with the weightmeasurement ratio of solvent; Temperature of reaction is-10～10 ℃.

9. the preparation method of citalopram according to claim 1-N-oxidation impurities (IV), citalopram (I) and the mol ratio 1: 1.0～2.5 of metachloroperbenzoic acid reaction citalopram (I) with metachloroperbenzoic acid, making citalopram-N-oxidation impurities (IV) extracts with mixed solvent, used solvent is selected from propyl carbinol, Virahol, ethanol, methyl alcohol, ethyl acetate, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, the mixing solutions of preferred propyl carbinol and ethyl acetate.

10. according to claim 1, the 9 described citalopram-N-oxidation impurities (IV) that make, adopt refining (the preferred propyl carbinol of eluent: ethyl acetate=1: 2～4) of method of silica gel column chromatography.