Preparation method of chiral sertraline hydrochloride

Abstract

The invention discloses a preparation method of chiral sertraline hydrochloride. The method comprises the steps that cis-sertraline hydrochloride and alkali of alkali metal salt containing D-mandelicacid are mixed and stirred in a solvent, after dehydration, inorganic salt is filtered out, a filtrate is cooled and crystallized, and solid-liquid separation is carried out; coarse D-mandelic acidsertraline is recrystallized, and solid-liquid separation is carried out; refined D-mandelic acid sertraline reacts with inorganic alkali in a mixed solvent of water and the organic solvent, and dehydration, crystallization and solid-liquid separation are carried out; a filtrate and hydrogen chloride are mixed and stirred in an organic solvent, after salification is completed, solid-liquid separation, washing and drying are carried to obtain the chiral sertraline hydrochloride. The preparation method of the chiral sertraline hydrochloride has the advantages that the alkali metal salt of the D-mandelic acid is taken as a resolving agent, the yield of cis-(1S,4S)-hydrochloride sertraline is high, the single organic solvent can be adopted in the entire process, the recovery rate of the alkalimetal salt of the D-mandelic acid and solvent is high, the alkali metal salt and the solvent can be recycled, and the preparation method is simple in operation, safe, environmentally friendly and suitable for industrial production.

Description

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of chiral sertraline hydrochloride. Background technique

[0002] Sertraline, CAS number: 79617-96-2, chemical name (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- N-methyl-1-naphthylamine is a selective serotonin reuptake inhibitor (SSRI). The structural formulas of sertraline and its isomers are shown below:

[0003]

[0004] Among them, the racemate formed by 1S-cis-sertraline and 1R-cis-sertraline is cis-(±)-sertraline (or racemic cis-sertraline); 1S-trans-sertraline The racemate formed by traline and 1R-trans-sertraline is trans-(±)-sertraline (or racemic trans-sertraline).

[0005] Sertraline hydrochloride is the hydrochloride salt of sertraline, with a CAS number of 79559-97-0. It is an antipsychotic depressant developed by Pfizer in the early 1990s. It has been listed in 96 countries and regions in the world so far. At present, it sti...

Examples

Embodiment 1

[0047] (1) 60 g of racemic cis-sertraline hydrochloride (the content of cis-(1S, 4S)-sertraline hydrochloride is 47%), 30.49 g of D-mandelic acid sodium salt, 130 g of n-butanol and 1.3 g of water g was added to a 500ml three-necked flask and reacted at 60°C for 3 hours, then heated up to distill off water, then heated to 118°C, filtered while hot to remove inorganic matter (mainly sodium chloride), rinsed with 10g of n-butanol, and combined to obtain filtrate 1 ;

[0048] (2) After the filtrate 1 was heated and completely dissolved, the temperature was lowered to 36.5° C., crystallized, centrifugally filtered, rinsed with 10 g of n-butanol to obtain the crude product of D-sertraline mandelate, and the combined liquids were obtained to obtain the filtrate 2;

[0049] (3) Mix the crude product of D-sertraline mandelate with 145g of n-butanol, heat up and dissolve completely, then cool down to 10°C, crystallize, centrifugally filter, rinse with 10g of n-butanol, and dry to obtai...

Embodiment 2

[0055] The preparation method of chiral sertraline hydrochloride is basically the same as in Example 1, except that the temperature in step (2) is lowered to 41°C.

[0056] Step (3), obtain 33.96g refined D-sertraline mandelic dry product;

[0057] In step (5), 23.18 g of cis-(1S,4S)-sertraline hydrochloride was obtained. The molar yield is 82.19%.

[0058] After testing, the purity of cis-(1S,4S)-sertraline hydrochloride was 99.51%, and the content was 99.87%.

[0059] In addition, 29.86 g of D-mandelic acid sodium salt was recovered according to the same method as in Example 1, and the molar recovery rate was 97.94%.

Embodiment 3

[0061] The preparation method of chiral sertraline hydrochloride is basically the same as in Example 1, except that the temperature in step (2) is lowered to 45°C.

[0062] Step (3), obtain 33.97g refined D-sertraline mandelic dry product;

[0063] In step (5), 23.15 g of cis-(1S,4S)-sertraline hydrochloride was obtained. The molar yield is 82.09%.

[0064] After testing, the purity of cis-(1S,4S)-sertraline hydrochloride was 99.49%, and the content was 99.61%.

[0065] In addition, 29.85 g of D-mandelic acid sodium salt was recovered according to the same method as in Example 1, and the molar recovery rate was 97.91%.

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of chiral sertraline hydrochloride. Background technique

[0002] Sertraline, CAS number: 79617-96-2, chemical name (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- N-methyl-1-naphthylamine is a selective serotonin reuptake inhibitor (SSRI). The structural formulas of sertraline and its isomers are shown below:

[0003]

[0004] Among them, the racemate formed by 1S-cis-sertraline and 1R-cis-sertraline is cis-(±)-sertraline (or racemic cis-sertraline); 1S-trans-sertraline The racemate formed by traline and 1R-trans-sertraline is trans-(±)-sertraline (or racemic trans-sertraline).

[0005] Sertraline hydrochloride is the hydrochloride salt of sertraline, with a CAS number of 79559-97-0. It is an antipsychotic depressant developed by Pfizer in the early 1990s. It has been listed in 96 countries and regions in the world so far. At present, it sti...

Examples

Embodiment 1

[0047] (1) 60 g of racemic cis-sertraline hydrochloride (the content of cis-(1S, 4S)-sertraline hydrochloride is 47%), 30.49 g of D-mandelic acid sodium salt, 130 g of n-butanol and 1.3 g of water g was added to a 500ml three-necked flask and reacted at 60°C for 3 hours, then heated up to distill off water, then heated to 118°C, filtered while hot to remove inorganic matter (mainly sodium chloride), rinsed with 10g of n-butanol, and combined to obtain filtrate 1 ;

[0048] (2) After the filtrate 1 was heated and completely dissolved, the temperature was lowered to 36.5° C., crystallized, centrifugally filtered, rinsed with 10 g of n-butanol to obtain the crude product of D-sertraline mandelate, and the combined liquids were obtained to obtain the filtrate 2;

[0049] (3) Mix the crude product of D-sertraline mandelate with 145g of n-butanol, heat up and dissolve completely, then cool down to 10°C, crystallize, centrifugally filter, rinse with 10g of n-butanol, and dry to obtai...

Embodiment 2

[0055] The preparation method of chiral sertraline hydrochloride is basically the same as in Example 1, except that the temperature in step (2) is lowered to 41°C.

[0056] Step (3), obtain 33.96g refined D-sertraline mandelic dry product;

[0057] In step (5), 23.18 g of cis-(1S,4S)-sertraline hydrochloride was obtained. The molar yield is 82.19%.

[0058] After testing, the purity of cis-(1S,4S)-sertraline hydrochloride was 99.51%, and the content was 99.87%.

[0059] In addition, 29.86 g of D-mandelic acid sodium salt was recovered according to the same method as in Example 1, and the molar recovery rate was 97.94%.

Embodiment 3

[0061] The preparation method of chiral sertraline hydrochloride is basically the same as in Example 1, except that the temperature in step (2) is lowered to 45°C.

[0062] Step (3), obtain 33.97g refined D-sertraline mandelic dry product;

[0063] In step (5), 23.15 g of cis-(1S,4S)-sertraline hydrochloride was obtained. The molar yield is 82.09%.

[0064] After testing, the purity of cis-(1S,4S)-sertraline hydrochloride was 99.49%, and the content was 99.61%.

[0065] In addition, 29.85 g of D-mandelic acid sodium salt was recovered according to the same method as in Example 1, and the molar recovery rate was 97.91%.

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