CN111303043A - Preparation method of flibanserin hydrochloride - Google Patents

Abstract

The invention relates to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of flibanserin hydrochloride. O-phenylenediamine and 3-trifluoromethylphenyl pyrazine are used as raw materials, wherein the o-phenylenediamine is reacted with ethyl acetoacetate to obtain a compound 10-1-G, a 3-trifluoromethylphenyl pyrazine compound I is subjected to two-step substitution reaction to obtain a compound 10-1-B, and the compound 10-1-B and the compound 10-1-G are subjected to substitution reaction to obtain a final product, namely flibanserin hydrochloride; aims at reducing cost, optimizing process and facilitating industrial production; the method has the advantages of simple and convenient operation, reasonable reaction flow, low production cost, good product quality, no pollution to the environment and suitability for industrial production, and the content is more than 99.5 percent.

Description

A kind of preparation method of flibanserin hydrochloride

technical field

The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of flibanserin hydrochloride.

Background technique

Flibanserin, a drug used to increase libido in women, reduces libido-suppressing serotonin to increase libido-stimulating dopamine levels. Germany's Boehringer Ingelheim announced the results of a phase 3 clinical trial of flibanserin at the European Society of Sexuality meeting on November 16, 2009, saying it was effective in premenopausal women with low libido (HSDD) Shows good efficacy and tolerability. The most critical intermediate, flibanserin hydrochloride, has great potential in its market prospects and economic benefits.

Flibanserin hydrochloride is reported in the literature [TURCONI M, BIETTI G, GIRALDO E, etal.Benzimidazo-lonederivatives as 5-HT1A and 5-HT2 antagonists:1993003016[P].1993-02-18.] The synthetic route of flibanserin is as follows: using 1-(1-phenylenyl)-1,3-dihydrobenzimidazolone as raw material, through alkylation and deprotection reaction, intermediates 2, 2 and 1 are obtained -(3-Trifluoromethylphenyl)piperazine hydrochloride condenses to give the intermediate flibanserin hydrochloride. However, the raw material 1-(1-phenylenyl)-1,3-dihydrobenzimidazolone is a rare and expensive commodity in the market, which has certain restrictions on the industrial production of flibanserin hydrochloride.

At present, there is no preparation method of flibanserin hydrochloride suitable for industry and low cost in the prior art.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a kind of preparation method of flibanserin hydrochloride suitable for industry and low cost in view of the defects and deficiencies of the prior art; be specifically related to the key intermediate flibanserin salt of flibanserin Synthesis of acid salts.

To achieve the above object, the technical scheme adopted in the present invention is: described flibanserin hydrochloride is specifically:

The preparation method steps of described flibanserin hydrochloride are as follows:

1. Using xylene as the solvent and KOH as the accelerator, the raw material o-phenylenediamine and ethyl acetoacetate are subjected to condensation reaction under the condition of 100°C-140°C, then crystallized at low temperature, and dried to obtain compound 10-1-G;

2. Dissolve the hydrochloride of 3-trifluoromethylphenylpyrazine in a mixed solvent of NaOH aqueous solution and acetone, and then react with bromoethanol at 50℃-70℃, extract and dry to obtain compound 10-1- E;

3. Compound 10-1-E is dissolved in dichloroethane, thionyl chloride is added dropwise, and a nucleophilic substitution reaction occurs at 70-90 ° C; ice-water cooling, and pH value adjustment, extraction, and drying to obtain compound 10 -1-B;

4. Compound 10-1-B and compound 10-1-G are subjected to nucleophilic substitution reaction at 60-80 ℃ with dimethyl sulfoxide as solvent and concentrated potassium carbonate as accelerator, and then extracted and dried to obtain flibanserin hydrochloride ;

Preferably, in the step 1, the molar ratio of o-phenylenediamine to ethyl acetoacetate is 1:0.9-1.2; the substitution reaction temperature is 105°C-150°C.

Preferably, in the step 2, the molar ratio of the hydrochloride, bromoethanol and NaOH of the compound 3-trifluoromethylphenylpyrazine is 1:1-1.5:1.5-4; the reaction temperature is 40°C-60°C °C.

Preferably, the molar ratio of compound 10-1-E to thionyl chloride in the step 3 is 1:2-4; the temperature is controlled at 60-80°C.

Preferably, the molar ratio of compound 10-1-B to compound 10-1-G and K ₂ CO ₃ in the step 4 is 1:0.9-1.1:2-3; the temperature is controlled at 50-70°C, This reaction uses dimethyl sulfoxide as solvent.

The technical idea of the present invention is: replace the 1-(1-phenylenyl)-1,3-dihydrobenzimidazolone reported in the literature with commercially available and cheap o-phenylenediamine as the starting material, Intermediate 10-1-G is obtained through condensation reaction, and intermediate 10-1-B is obtained by two-step substitution reaction with 3-trifluoromethylphenylpyrazine, and the two intermediates undergo substitution reaction to obtain the final product , namely flibanserin hydrochloride.

Compared with the prior art, the advantages and beneficial effects of the technical solution of the present invention are:

1. The 1-(1-phenylenyl)-1,3-dihydrobenzimidazolone reported in the literature is replaced by commercially available o-phenylenediamine as the starting material, which makes industrial implementation easier.

2. Due to the low price of the raw material o-phenylenediamine, the production cost of the final product is about 50% of the original cost.

3. The product quality is good, the content is more than 99.5%, no pollution to the environment, suitable for industrial production.

Detailed ways

The flibanserin hydrochloride described in this specific embodiment is specifically:

Example 1:

A preparation method of flibanserin hydrochloride, the steps are as follows:

1. Synthesis of compound 10-1-G

3kg of o-phenylenediamine, 4.5kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene were put into a 50L oil bath heating kettle, heated to 120 ° C, refluxed for 2 hours, crystallized by cooling, suction filtered, rinsed with a small amount of xylene , the wet weight of 4.2kg10-1-G was obtained as a gray solid, the product was confirmed by NMR, and the yield was 81%.

2. Synthesis of compound 10-1-E

The hydrochloride 5kg of 3-trifluoromethylphenylpyrazine was dissolved in 2.873kg NaOH 12.5L aqueous solution, and 12.5L acetone was added to the 50L reactor, stirred at room temperature, and then added 2-bromoethanol 3.843kg, 60 ℃ The reaction was carried out at the same temperature for 4 hours. After the reaction was completed, the acetone was spin-dried, then 20 L of water was added, extracted with dichloromethane three times, the dichloromethane extracts were combined, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and spin Dried 5Kg of pale yellow liquid 10-1-E. The product was confirmed by NMR, and the yield was 95%.

3. Synthesis of compound 10-1-B

2.5kg of 10-1-E was dissolved in 25L of dichloroethane, 3.931Kg of SOCl ₂ was added dropwise at room temperature, and the mixture was heated to 80° C. to react for 4 hours. The reaction solution was poured into 25L of ice water, adjusted to pH 10 with NaOH solution, extracted twice with dichloromethane, combined with organic phases, dried and filtered with silica gel once, and spin-dried to obtain 2.35kg of dark oily substance 10-1-B. The product was confirmed by NMR, and the yield was 88%.

4. Synthesis of the compound flibanserin hydrochloride

10-1-G 2.385KG, 10-1-B 4.534KG, K ₂ CO ₃ 5.27KG and dimethyl sulfoxide 18L were added to a 50L oil bath kettle, and reacted at 70°C for 8 hours. TLC showed that the reaction of the raw materials was completed. , the reaction solution was poured into water, extracted three times with dichloromethane, the organic phases were combined, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a gray solid.

The gray solid was dissolved by heating with 25L of ethanol, added 6L of concentrated HCl, reacted at 70°C for 2 hours, the reaction was completed, the reaction solution was released, 15L of ethanol was added, cooled to room temperature, the solid was precipitated, suction filtered, and rinsed with ethanol to obtain 4.4kg of white solid. The product was confirmed by NMR, and the yield was 76%.

Embodiment 2:

A preparation method of flibanserin hydrochloride, the steps are as follows:

1. Synthesis of compound 10-1-G

3kg of o-phenylenediamine, 4.1kg of ethyl acetoacetate, 100ml of KOH solution and 19L of xylene were put into a 50L oil bath heating kettle, heated to 140 ° C, refluxed for 2 hours, crystallized by cooling, suction filtered, rinsed with a small amount of xylene , the wet weight of 4.2kg10-1-G was obtained as a gray solid, the product was confirmed by NMR, and the yield was 80%.

2. Synthesis of compound 10-1-E

The hydrochloride 5kg of 3-trifluoromethylphenylpyrazine was dissolved in 2.973kg NaOH 12.5L aqueous solution, and 12.5L acetone was added to the 50L reactor, stirred at room temperature, and then added 3.943kg of 2-bromoethanol, 70° C. The reaction was carried out at the same temperature for 4 hours. After the reaction was completed, the acetone was spin-dried, then 20 L of water was added, extracted with dichloromethane 4 times, the dichloromethane extracts were combined, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and rotated Dried 5Kg of pale yellow liquid 10-1-E. The product was confirmed by NMR, and the yield was 94%.

3. Synthesis of compound 10-1-B

Dissolve 2.5kg of 10-1-E in 25L of dichloroethane, add 4.00Kg of SOCl ₂ dropwise at room temperature, and heat to 70° C. to react for 4 hours after dropping. The reaction solution was poured into 25L of ice water, adjusted to pH 10 with NaOH solution, extracted with dichloromethane 3 times, combined with organic phases, dried and filtered with silica gel once, and spin-dried to obtain 2.45kg of dark oily substance 10-1-B. The product was confirmed by NMR, and the yield was 8805%.

4. Synthesis of the compound flibanserin hydrochloride

10-1-G 2.485KG, 10-1-B 4.634KG, K ₂ CO ₃ 5.37KG and dimethyl sulfoxide 18L were added to a 50L oil bath kettle, and reacted for 8 hours under the condition of 65°C. TLC showed that the reaction of the raw materials was completed. , the reaction solution was poured into water, extracted three times with dichloromethane, the organic phases were combined, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a gray solid.

The gray solid was dissolved by heating with 25L of ethanol, added 6L of concentrated HCl, and reacted at 68°C for 2 hours. After the reaction was completed, the reaction solution was released, and 15L of ethanol was added, cooled to room temperature, and the solid was precipitated, filtered with suction, and rinsed with ethanol to obtain 4.4kg of white solid. The product was confirmed by NMR, and the yield was 75.5%.

Embodiment three:

A preparation method of flibanserin hydrochloride, the steps are as follows:

1. Synthesis of compound 10-1-G

3kg of o-phenylenediamine, 3.8kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene were put into a 50L oil bath heating kettle, heated to 140 ° C, refluxed for 2 hours, crystallized by cooling, suction filtered, rinsed with a small amount of xylene , 4.2kg 10-1-G was obtained as a gray solid wet weight, the product was confirmed by NMR, and the yield was 83%.

2. Synthesis of compound 10-1-E

The hydrochloride 5kg of 3-trifluoromethylphenylpyrazine was dissolved in 2.773kg NaOH 12.5L aqueous solution, and 12.5L acetone was added to the 50L reactor, stirred at room temperature, and then added 3.743kg of 2-bromoethanol, 50° C. The reaction was carried out at the same temperature for 4 hours. After the reaction was completed, the acetone was spin-dried, then 20 L of water was added, extracted with dichloromethane three times, the dichloromethane extracts were combined, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and spin Dried 5Kg of pale yellow liquid 10-1-E. The product was confirmed by NMR, and the yield was 94%.

3. Synthesis of compound 10-1-B

Dissolve 2.5kg of 10-1-E in 25L of dichloroethane, add 3.831Kg of SOCl ₂ dropwise at room temperature, and heat to 75° C. to react for 4 hours after dropping. The reaction solution was poured into 25L of ice water, adjusted to pH 10 with NaOH solution, extracted twice with dichloromethane, combined with organic phases, dried and filtered with silica gel once, and spin-dried to obtain 2.35kg of dark oily substance 10-1-B. The product was confirmed by NMR, and the yield was 87.5%.

4. Synthesis of the compound flibanserin hydrochloride

10-1-G 2.285KG, 10-1-B 4.434KG, K ₂ CO ₃ 5.17KG and dimethyl sulfoxide 18L were added to a 50L oil bath kettle, and reacted at 58°C for 8 hours. TLC showed that the reaction of the raw materials was completed. , the reaction solution was poured into water, extracted 3 times with dichloromethane, the organic phases were combined, washed 3 times with water, once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a gray solid.

The gray solid was dissolved by heating with 25L of ethanol, added 6L of concentrated HCl, reacted at 65°C for 2 hours, the reaction was completed, the reaction solution was released, 15L of ethanol was added, cooled to room temperature, a solid was precipitated, suction filtered, and rinsed with ethanol to obtain 4.4kg of white solid. The product was confirmed by NMR, and the yield was 77%.

The purpose of the present invention is to reduce costs, optimize the process, and facilitate industrialized production. The principle is to use o-phenylenediamine and 3-trifluoromethylphenylpyrazine as raw materials, wherein o-phenylenediamine is reacted with ethyl acetoacetate to obtain compound 10-1-G, 3-trifluoromethylphenylpyrazine The oxazine compound I is subjected to two-step substitution reaction to obtain compound 10-1-B, and compound 10-1-B and 10-1-G are subjected to substitution reaction to obtain the final product compound flibanserin hydrochloride. The method has the advantages of simple and convenient operation, reasonable reaction process, low production cost, good product quality, content of more than 99.5%, no pollution to the environment, and is suitable for industrial production.

The above is only used to illustrate the technical solution of the present invention and not to limit it. Other modifications or equivalent replacements made by those of ordinary skill in the art to the technical solution of the present invention, as long as they do not depart from the spirit and scope of the technical solution of the present invention, should be Included within the scope of the claims of the present invention.

Claims (6)

1. A preparation method of flibanserin hydrochloride is characterized by comprising the following steps: the flibanserin hydrochloride is:

the preparation method comprises the following steps:

(1) the method comprises the following steps of taking dimethylbenzene as a solvent and KOH as an accelerator, carrying out condensation reaction on o-phenylenediamine and ethyl acetoacetate serving as raw materials at the temperature of 100-140 ℃, then crystallizing at low temperature, and drying to obtain a compound 10-1-G;

(2) dissolving hydrochloride of the 3-trifluoromethyl phenyl pyrazine in a mixed solvent of NaOH aqueous solution and acetone, performing substitution reaction with bromoethanol at 50-70 ℃, and extracting and drying to obtain a compound 10-1-E;

(3) dissolving the compound 10-1-E in dichloroethane, dropwise adding thionyl chloride, and carrying out nucleophilic substitution reaction at 70-90 ℃; cooling with ice water, adjusting pH value, extracting, and drying to obtain compound 10-1-B;

(4) and performing nucleophilic substitution reaction on the compound 10-1-B and the compound 10-1-G at the temperature of 60-80 ℃ by using dimethyl sulfoxide as a solvent and concentrated potassium carbonate as an accelerator, and extracting and drying to obtain flibanserin hydrochloride.

2. The process according to claim 1, characterized in that: in the step 1, the molar ratio of the usage amount of o-phenylenediamine to the usage amount of ethyl acetoacetate is 1: 0.9-1.2; the temperature of the substitution reaction is 105-150 ℃.

3. The process according to claim 1, characterized in that: the use molar ratio of hydrochloride of the compound 3-trifluoromethyl phenyl pyrazine in the step 2 to the use amount of bromoethanol to NaOH is 1: 1-1.5: 1.5-4; the reaction temperature is 40-60 ℃.

4. The process according to claim 1, characterized in that: the molar ratio of the compound 10-1-E to the thionyl chloride in the step 3 is 1: 2-4; the temperature is controlled at 60-80 ℃.

5. The process according to claim 1, characterized in that: the compound in the step 410-1-B and Compounds 10-1-G and K₂CO₃The molar ratio of the used amount is 1: 0.9-1.1: 2-3; the temperature is controlled at 50-70 ℃, and dimethyl sulfoxide is used as a solvent in the reaction.

6. The process according to claim 1, characterized in that: the preparation method comprises the following steps:

(1) synthesis of Compound 10-1-G

Putting 3kg of o-phenylenediamine, 4.5kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene into a 50L oil bath heating kettle, heating to 120 ℃, carrying out reflux reaction for 2 hours, cooling, crystallizing, carrying out suction filtration, rinsing with a small amount of xylene to obtain 4.2kg of 10-1-G of gray solid wet weight, and confirming the yield of 81% of a product by nuclear magnetism;

(2) synthesis of Compound 10-1-E

Dissolving 5Kg of hydrochloride of 3-trifluoromethylphenylpyrazine in 2.873Kg of NaOH12.5L aqueous solution, adding 12.5L of acetone into a 50L reaction kettle, stirring at room temperature, adding 3.843Kg of 2-bromoethanol, reacting for 4 hours at 60 ℃, after the reaction is finished, spin-drying the acetone, adding 20L of water, extracting for 3 times by using dichloromethane, combining dichloromethane extract liquor, washing for 2 times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 5Kg of light yellow liquid 10-1-E; the product is verified by nuclear magnetism, and the yield is 95%;

(3) synthesis of Compound 10-1-B

2.5kg of 10-1-E were dissolved in 25L of dichloroethane, and SOCl was added dropwise at room temperature₂3.931Kg, and the mixture is heated to 80 ℃ after dropping to react for 4 hours. The reaction solution was poured into 25L of ice water, the pH was adjusted to about 10 with NaOH solution, extracted 2 times with dichloromethane, the organic phases were combined, dried, filtered once with silica gel and spin-dried to give 2.35kg10-1-B as a dark oil. The product is verified by nuclear magnetism, and the yield is 88%;

(4) and synthesis of flibanserin hydrochloride

10-1-G2.385KG、10-1-B4.534KG、K₂CO₃Adding 5.27KG and 18L dimethyl sulfoxide into 50L oil bath kettle, reacting at 70 deg.C for 8 hr, TLC showing that the raw materials are reacted completely, pouring the reaction solution into water, extracting with dichloromethane for 3 times, and mixingWashing the organic phase with water for 2 times, washing the organic phase with saturated saline solution for one time, drying the organic phase with anhydrous sodium sulfate, and spin-drying the organic phase to obtain a gray solid;

dissolving gray solid in 25L of ethanol under heating, adding 6L of concentrated HCl, reacting at 70 deg.C for 2 hr, discharging reaction solution, adding 15L of ethanol, cooling to room temperature, separating out solid, vacuum filtering, and rinsing with ethanol to obtain white solid 4.4 kg; the product is verified by nuclear magnetism, and the yield is 76%.