Method for racemization recovery of citalopram splitting process mother liquor

Abstract

The invention discloses a method for racemization recovery of mother liquor in a citalopram resolution process, which comprises the following steps: carrying out esterification reaction on the resolution mother liquor and ester forming acyl chloride under the condition of an acid-binding agent, hydrolyzing by using sodium hydroxide, and resolving by using a resolving agent to obtain an escitalopram oxalate intermediate. The resolution yield is high, the resolution cost is low, and the production cost of the raw material medicine can be effectively reduced.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a method for recovering racemization of mother liquor in a citalopram splitting process. Background Art

[0002] Citalopram is a selective serotonin reuptake inhibitor (SSRI), a racemic form, which can selectively inhibit the 5-HT transporter, block the reuptake of 5-HT by the presynaptic membrane, prolong and increase the action of 5-HT, and thus produce an antidepressant effect. Escitalopram oxalate belongs to the SSRIs class of antidepressants. Its main indication is the treatment of major depressive disorder, and it can also treat chronic major depressive disorder with dysthymia; the second indication of escitalopram oxalate is the treatment of obsessive-compulsive disorder. The dose for the treatment of obsessive-compulsive disorder is higher than that for the treatment of depression, and the reaction latency is usually longer; escitalopram oxalate can also treat most anxiety disorders, including panic disorder, social anxiety disorder, generalized anxiety disorder, and post-traumatic stress disorder. Compared with citalopram, escitalopram oxalate has fewer side effects and a faster therapeutic effect.

[0003] In the preparation process of escitalopram oxalate, the intermediate 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile needs to undergo a one-step splitting process, that is, the racemized 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is split into an S-configuration product, and then undergoes a free reaction, a ring-closing reaction, and finally forms a salt with oxalic acid to obtain the escitalopram oxalate product, as shown in Formula 1. The configuration required in the splitting process is the S configuration, but the yield of the splitting of this configuration is only 30-40%; the proportions of the R configuration and the S configuration in the splitting mother liquor are approximately 70% and 30%, and these mother liquors are treated and wasted in the form of waste liquid. If the split mother liquor is racemized and recovered, so that the proportion of R configuration and S configuration becomes 50% and 50%, the product in the split mother liquor can be used as the raw material 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to continue the split reaction, so that an additional 30-40% of S configuration product can be obtained, which greatly reduces the cost. Therefore, it is urgent to develop a method for racemizing and recovering the split mother liquor of the intermediate 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile, so as to reduce the split cost, reduce the production cost of the raw material drug, and realize the promotion and application of the preparation.

[0004] Summary of the invention

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for racemization recovery of mother liquor in a citalopram splitting process, which has high splitting yield, reduces splitting cost, and reduces the production cost of raw materials.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A method for racemization recovery of mother liquor in a Citalopram splitting process comprises the following steps:

[0008] (1) Preparation of compound 1: 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (R configuration and S configuration account for about 70% and 30%) in the mother liquor is subjected to esterification reaction with ester-forming acid chloride in the presence of an acid-binding agent to produce compound 1;

[0009]

[0010] (2) Preparation of compound 2: Compound 1 was hydrolyzed with sodium hydroxide in a methanol / water system to obtain compound 2;

[0011]

[0012] (3) Preparation of Compound 3: Compound 2 was split using a splitting agent to obtain Compound 3 of S configuration, which is an intermediate of escitalopram oxalate: (-)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile·corresponding splitting agent salt (the splitting agent is one of D-(+)-dibenzoyltartaric acid, D-(+)-di-p-toluoyltartaric acid, D-tartaric acid or D-mandelic acid).

[0013]

[0014] In step (1), the ester-forming acyl chloride is pivaloyl chloride, methylsulfonyl chloride or chloroacetyl chloride; preferably pivaloyl chloride.

[0015] In step (1), the molar ratio of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to the ester-forming acid chloride is 1:(2.0-3.5), preferably 1:(2.5-3.0), and more preferably 1:2.7.

[0016] In step (1), the molar ratio of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to the acid binding agent is 1:(3.0-5.0), preferably 1:(3.5-4.5), and more preferably 1:4.0.

[0017] In step (1), the acid-binding agent is an organic base, preferably one or a mixture of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine, and more preferably triethylamine.

[0018] In step (1), the reaction is carried out in a solvent, which is a halogenated hydrocarbon, an ester or a benzene, preferably toluene; and the reaction temperature is -20 to 10°C, preferably -10 to 0°C.

[0019] In step (2), the molar ratio of compound 1 to sodium hydroxide is 1:(2.0-3.0), preferably 1:(2.0-2.5), and more preferably 1:2.2.

[0020] In step (2), the reaction temperature is 0 to 70°C, preferably 40 to 50°C.

[0021] In step (3), the resolving agent is D-(+)-dibenzoyltartaric acid, D-(+)-di-p-toluoyltartaric acid, D-tartaric acid or D-mandelic acid, preferably D-(+)-di-p-toluoyltartaric acid.

[0022] In step (3), the molar ratio of compound 2 to the resolving agent is 1:(0.25-1.0), preferably 1:0.60.

[0023] In step (3), the separation is carried out in a solvent, and the solvent is methanol, ethanol, isopropanol or acetonitrile, preferably isopropanol; the reaction temperature is 30 to 80°C, preferably 40 to 50°C.

[0024] The principle of the present invention is: first, 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile (wherein the R configuration and the S configuration account for about 70% and 30%) in the resolution mother liquor undergoes an esterification reaction with an ester-forming acyl chloride to convert the optical isomer into a racemized ester (i.e., compound 1); then, the racemized ester (i.e., compound 1) undergoes a hydrolysis reaction to convert into compound 2 (4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile, where the R configuration and the S configuration account for about 50% and 50%; finally, a resolving agent is used to resolve compound 2 to obtain compound 3 of S configuration.

[0025] Compared with the prior art, the present invention has the following advantages and effects:

[0026] (1) The present invention adopts ester-forming acyl chloride to carry out esterification reaction, which is cheap, easy to operate, has high reaction conversion rate and selectivity, and does not produce excessive by-products.

[0027] (2) The present invention uses esterification reaction to carry out racemization and then hydrolysis to obtain the raw material before separation. In addition, the operation is very simple in the process of scaled-up production, with short working hours and without occupying too much production equipment and energy consumption.

[0028] (3) The present invention recovers and splits the mother liquor through racemization, which greatly reduces the cost of the escitalopram oxalate production process. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The HPLC (normal phase) detection spectrum of the mother solution of the present invention is shown.

[0030] Figure 2 This is the HPLC (normal phase) detection spectrum of compound 1.

[0031] Figure 3 This is the HPLC (normal phase) detection spectrum of compound 2.

[0032] Figure 4 This is the HPLC (normal phase) detection spectrum of compound 3. DETAILED DESCRIPTION

[0033] In order to facilitate the understanding of the present invention, the present invention will be described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be pointed out that, for those skilled in the art, without departing from the inventive concept, the present invention can also make some variations and improvements, which all belong to the protection scope of the present invention.

[0034] Example 1: Preparation of Compound 1

[0035] 600 ml of the split mother liquor containing 100.00 g of the product 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile·D-(+)-di-p-toluoyl tartrate (DTTA salt for short) (0.187 mol) was concentrated under reduced pressure at a temperature of 40-50° C., evaporated to dryness, stirred with 50 ml of toluene, and concentrated again under reduced pressure, evaporated to dryness again, added with 400 ml of toluene, stirred and dispersed, added with 89.76 g of 10% aqueous sodium hydroxide solution (0.224 mol), stirred at a temperature of 40-45° C. for 4 hours, separated, the organic phase was washed with 50 ml of drinking water, and the upper organic phase was dried with 5.00 g of anhydrous sodium sulfate.

[0036] The obtained organic phase was added with 75.69g triethylamine (0.748mol), the temperature was controlled at -10 to 0°C, and a mixture of 60.89g pivaloyl chloride (0.505mol) and 60.9ml toluene was added dropwise. After the addition, the mixture was stirred at -10 to 0°C for 2 to 3h. TLC showed that all the raw materials were converted. 400ml of drinking water was added, stirred and separated, and the organic phase was washed with 200ml saturated brine, concentrated under reduced pressure at 45 to 55°C, evaporated to dryness, added with 300ml n-heptane, stirred and crystallized, filtered, and the filter cake was washed with 50ml n-heptane. The product was dried in vacuo at 40°C to obtain compound 1 as a pale yellow solid of 82.12g with a yield of 86.2% and a purity (HPLC): 96.4%.

[0037] Figure 1 This is the HPLC (normal phase) detection spectrum of the split mother liquor. From the monitoring data in the figure, it can be seen that the ratio of the S-configuration product to the R-configuration product in the split mother liquor is about 30%:70%. Figure 2 This is the detection spectrum of compound 1 by HPLC (normal phase), and it can be seen that the ratio of the products of S configuration and R configuration in compound 1 after esterification is about 50%:50%.

[0038] Example 2: Preparation of Compound 1

[0039] 600 ml of split mother liquor containing 100.00 g of product DTTA salt (0.187 mol) was concentrated under reduced pressure at 40-50° C. after evaporation to dryness, stirred with 50 ml of toluene and concentrated again under reduced pressure. Evaporated to dryness again, added with 400 ml of toluene and stirred to disperse, added with 89.76 g of 10% aqueous sodium hydroxide solution (0.224 mol), stirred at 40-45° C. for 4 h, separated, the organic phase was washed with 50 ml of drinking water, and the upper organic phase was dried with 5.00 g of anhydrous sodium sulfate.

[0040] 56.77g triethylamine (0.561mol) was added to the obtained organic phase, and a mixture of 45.10g pivaloyl chloride (0.374mol) and 45.1ml toluene was added dropwise at a temperature of -20 to -10°C. After the addition, the mixture was stirred and reacted for 3 to 5h at a temperature of -20 to -10°C. TLC showed that the raw material had almost no color. 400ml of drinking water was added, stirred and separated, and the organic phase was washed with 200ml saturated brine, concentrated under reduced pressure at a temperature of 45 to 55°C, evaporated to dryness, added with 300ml of n-heptane, stirred and crystallized, filtered, and the filter cake was washed with 50ml of n-heptane. The product was dried in vacuo at 40°C to obtain compound 1 as a light yellow solid of 73.83g with a yield of 77.5% and a purity (HPLC): 93.1%.

[0041] Example 3: Preparation of Compound 1

[0042] 600 ml of split mother liquor containing 100.00 g of product DTTA salt (0.187 mol) was concentrated under reduced pressure at 40-50° C. after evaporation to dryness, stirred with 50 ml of toluene and concentrated again under reduced pressure. Evaporated to dryness again, added with 400 ml of toluene and stirred to disperse, added with 89.76 g of 10% aqueous sodium hydroxide solution (0.224 mol), stirred at 40-45° C. for 4 h, separated, the organic phase was washed with 50 ml of drinking water, and the upper organic phase was dried with 5.00 g of anhydrous sodium sulfate.

[0043] 94.61 g of triethylamine (0.935 mol) was added to the obtained organic phase, and a mixture of 78.93 g of pivaloyl chloride (0.654 mol) and 78.9 ml of toluene was added dropwise at a temperature of 0 to 10 ° C. After the addition was completed, the mixture was stirred and reacted at 0 to 10 ° C for 1 h. TLC showed that the raw material was completely converted. 600 ml of drinking water was added, stirred and separated, and the organic phase was washed with 200 ml of saturated brine, concentrated under reduced pressure at a temperature of 45 to 55 ° C. After evaporation, 300 ml of n-heptane was added, stirred and crystallized, filtered, and the filter cake was washed with 50 ml of n-heptane. The product was dried in vacuo at 40 ° C. The compound 1 was obtained as a light yellow solid of 81.74 g with a yield of 85.8% and a purity (HPLC): 95.3%.

[0044] Example 4: Preparation of Compound 2

[0045] To 50.00g of compound 1 (97.9mmol), 200ml of methanol was added, stirred and dissolved, 43.08g of 20% aqueous sodium hydroxide solution (215mmol) was added, the temperature was raised to 40-50℃, and the reaction was stirred for 4-5h. TLC showed that compound 1 disappeared, and the reaction solution was concentrated under reduced pressure at 40-50℃. After the methanol was basically evaporated, 200ml of dichloromethane was added, and 300ml of drinking water was stirred and extracted. The organic phase was washed with 100ml of saturated brine, and the organic phase was concentrated under reduced pressure at 40℃ to dryness to obtain about 34g of a red oil, i.e., compound 2, which was put into the next step with a theoretical yield of 100%.

[0046] like Figure 3 The graph shows the detection spectrum of compound 2 by HPLC (normal phase). The ratio of S-configuration to R-configuration products in the hydrolyzed compound 2 is about 50%:50%. The compound is the intermediate before the resolution of escitalopram oxalate (4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile.

[0047] Example 5: Preparation of Compound 2

[0048] To 50.00g of compound 1 (97.9mmol), add 200ml of methanol, stir to dissolve, add 58.8g of 20% aqueous sodium hydroxide solution (294mmol), heat to 30-40℃ and stir to react for 6-7h. TLC shows that compound 1 disappears. Control the temperature at 40-50℃ and concentrate the reaction solution under reduced pressure. After the methanol is basically evaporated to dryness, add 200ml of dichloromethane and stir to extract with 300ml of drinking water. Wash the organic phase with 100ml of saturated brine. Control the temperature at 40℃ and concentrate under reduced pressure to dryness to obtain about 33g of a red oily substance, i.e., compound 2, which is put into the next step with a theoretical yield of 100%.

[0049] Example 6: Preparation of Compound 3

[0050] To a bottle containing compound 2 (97.9 mmol), 134.09 g of isopropanol was added, the temperature was raised to 40-50 ° C, and the mixture was stirred and dissolved. After the mixture was dissolved, 22.69 g of D-di-p-methylbenzoyltartaric acid (58.7 mmol) was added, and the mixture was stirred and dissolved. The mixture was gradually precipitated. After the precipitation, the mixture was kept at 40-50 ° C for 1 h to grow the crystals. The mixture was cooled to 15-25 ° C for about 3-4 h and kept for crystallization for 3 h. The mixture was filtered, and the filter cake was rinsed with 10 g of isopropanol. The product was dried in vacuo at 60 ° C to obtain compound 3 as a white solid (15.99 g). The yield was 30.5%, the purity (HPLC): 99.758%, and the isomers (HPLC): 98.823%.

[0051] like Figure 4 The graph shown is the detection spectrum of compound 3 by HPLC (normal phase). The isomer content of the resolved product is about 1-1.5%, and the content of the target S-configuration product is about 99%, that is, the important intermediate of escitalopram oxalate after resolution is obtained.

[0052] Example 7: Preparation of Compound 3

[0053] To a bottle containing compound 2 (97.9 mmol), 134.09 g of isopropanol was added, the temperature was raised to 40-50 ° C, and stirred to dissolve. After the solution was clear, 30.25 g of D-di-p-methylbenzoyltartaric acid (78.3 mmol) was added, and the solution was stirred and dissolved at a temperature of 40-50 ° C., and then gradually precipitated. After precipitation, the crystal was grown at 40-50 ° C for 1 h, and then the temperature was lowered to 15-25 ° C for about 3-4 h and the crystal was kept at a temperature of 3 h. The filter cake was washed with 10 g of isopropanol, and the product was dried in vacuo at 60 ° C to obtain compound 3, and 17.41 g of a white solid was obtained, with a yield of 33.2%, a purity (HPLC): 99.697%, and an isomer (HPLC): 98.037%.

[0054] Example 8: Preparation of Compound 3

[0055] To a bottle containing compound 2 (97.9 mmol), 134.09 g of isopropanol was added, the temperature was raised to 50-60 ° C, and the mixture was stirred and dissolved. After the mixture was dissolved, 13.40 g of D-mandelic acid (88.1 mmol) was added, and the mixture was stirred and dissolved. The mixture was gradually precipitated. After the precipitation, the mixture was kept at 50-55 ° C for 1 h to grow crystals. The mixture was then cooled to 25-35 ° C for about 3-4 h and kept for crystallization for 3 h. The mixture was filtered, and the filter cake was rinsed with 10 g of isopropanol. The product was dried in vacuo at 60 ° C to obtain compound 3. 13.42 g of a white solid was obtained. The yield was 25.6%, the purity (HPLC): 99.632%, and the isomers (HPLC): 97.655%.

Claims

1. A method for recovering the mother liquor from the racemization of Citalopram separation process, characterized in that The following steps are involved: (1) Preparation of compound 1: 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile in the resolved mother liquor undergoes an esterification reaction with an ester-forming acid chloride in the presence of an acid-binding agent to produce compound 1; (2) Preparation of compound 2: Compound 1 was hydrolyzed with sodium hydroxide in a methanol / water system to obtain compound 2; (3) Preparation of compound 3: Compound 2 is split using a splitting agent to obtain compound 3 of S configuration, which is an intermediate of escitalopram oxalate; 2. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (1), the ester-forming acyl chloride is pivaloyl chloride, methanesulfonyl chloride or chloroacetyl chloride.

3. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (1), the molar ratio of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to the ester-forming acid chloride is 1:(2.0-3.5).

4. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (1), the molar ratio of 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile to the acid binding agent is 1:(3.0-5.0).

5. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (1), the acid binding agent is one or a mixture of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, and pyridine.

6. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (1), the reaction is carried out in a solvent, which is a halogenated hydrocarbon, an ester or a benzene; and the reaction temperature is -20 to 10°C.

7. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (2), the molar ratio of compound 1 to sodium hydroxide is 1:(2.0-3.0); and the reaction temperature is 0-70°C.

8. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (3), the resolving agent is D-(+)-dibenzoyltartaric acid, D-(+)-di-p-toluoyltartaric acid, D-tartaric acid or D-mandelic acid.

9. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (3), the molar ratio of compound 2 to the resolving agent is 1:(0.25-1.0).

10. The method for racemization and recovery of mother liquor in the separation process of Citalopram according to claim 1, characterized in that: In step (3), the separation is carried out in a solvent, which is methanol, ethanol, isopropanol or acetonitrile; and the reaction temperature is 30 to 80°C.

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