A method for preparing brexpiprazole
By optimizing the synthetic route of buripiperazole, the intermediate I-1 was generated by reacting compound SM-1 with SM-2, and then constructed with SM-3 to form a piperazine ring. This solved the problems of low purity and yield of buripiperazole and enabled efficient industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- LUNAN PHARMA GROUP CORPORATION
- Filing Date
- 2024-11-29
- Publication Date
- 2026-05-29
AI Technical Summary
Existing processes for synthesizing buripiperazole suffer from low purity and low yield of intermediates and target products, high production costs, and difficulty in obtaining starting materials.
Compound SM-1 and SM-2 were reacted in the presence of acid-binding agent A to generate intermediate I-1, which was then reacted with SM-3 in the presence of acid-binding agent B to construct a piperazine ring, thus preparing bripiprazole I. The reaction conditions and solvent selection were optimized to improve purity and yield.
This method achieves high purity and high yield of biriperazole, making it suitable for industrial production, simplifying the operation process, and reducing production costs.
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing birepiperazole. Background Technology
[0002] Biriperazole is an experimental serotonin-dopamine activity modulator (SDAM), a novel multi-target mechanism of action drug for the treatment of mental disorders. It was launched in the United States in 2015. In addition to its primary dopamine D2 receptor agonist activity, it also exhibits partial D3 receptor agonist activity and 5-HT activity. 1A Partial receptor agonism and 5-HT 2A This drug, with partial receptor antagonism, is a novel medication developed targeting multiple sites of monoamine neurotransmitters, exhibiting both antipsychotic and antidepressant effects. It offers better efficacy and tolerability, reducing adverse reactions such as akathisia, restlessness, and / or insomnia. Clinically, it is primarily used as adjunctive therapy for schizophrenia and major depressive disorder.
[0003] Chinese invention patent CN105461703B uses 4-aminobenzo[b]thiophene as a starting material, reacting it with bis(2-chloroethyl)amine under the action of PTSA (p-toluenesulfonamide) to construct a piperazine ring, yielding the key intermediate 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride, which is then reacted with 7-(4-chlorobutoxy)-1H-quinoline-2-one to obtain the target product. However, the purity of both the intermediate and the target product obtained by this process is low. The synthetic route is shown below:
[0004]
[0005] Chinese invention patent application CN106831739A uses 4-nitrobenzene[b]thiophene as a starting material, catalytically hydrogenating and reducing the nitro group to obtain 4-aminobenzo[b]thiophene. Using 7-hydroxy-1H-quinoline-2-one as another starting material, it first reacts with 1-bromo-4-chlorobutane to generate 7-(4-chlorobutoxy)-1H-quinoline-2-one, then reacts with diethanolamine in the presence of potassium carbonate. The hydroxyl group is then activated by methanesulfonyl chloride acylation, and finally ring-closed with 4-aminobenzo[b]thiophene to obtain the target product, bripiprazole. However, this process requires further activation of the hydroxyl group, increasing the number of unit operations. Furthermore, the starting material 4-nitrobenzene[b]thiophene is not readily available, resulting in high production costs. The synthetic route is shown below:
[0006]
[0007] Given the numerous technical problems existing in the above-mentioned process for preparing biriperazole, researching and finding a safe, simple process route for producing biriperazole with high yield and high purity to ensure the production, market supply and quality of related products remains one of the problems that need to be solved. Summary of the Invention
[0008] To address the numerous problems existing in the preparation of birepiperazole in current technologies, this invention provides a novel method for preparing birepiperazole. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and high yield.
[0009] The specific technical solution of the present invention is as follows:
[0010]
[0011] A method for preparing birepiperazole as shown in Formula I includes the following steps:
[0012] Step 1: Preparation of compound I-1
[0013] Compounds SM-1, SM-2, and acid-binding agent A were added to reaction solvent A, and the reaction was carried out at a controlled temperature T1. After the reaction was completed, the reaction solution was poured into purified water, and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1. The synthetic route is shown below:
[0014]
[0015] Preferably, the acid-binding agent A mentioned in step 1 is selected from one or a combination of sodium bicarbonate, pyridine, triethylamine, and N,N-diisopropylethylamine, with triethylamine being particularly preferred.
[0016] Preferably, the molar ratio of compound SM-1, compound SM-2, and acid-binding agent in step 1 is 1:2.1-3.0:2.5-4.0; particularly preferably 1:2.2:3.5.
[0017] Preferably, the reaction solvent A in step 1 is selected from one or a combination of dichloromethane, chloroform, and toluene, with chloroform being particularly preferred.
[0018] Preferably, the reaction temperature T1 in step 1 is 30-70°C, and more preferably 55-60°C.
[0019] Step 2: Preparation of Compound I
[0020] Compounds SM-3, I-1, and acid-binding agent B were added to reaction solvent B, and the reaction was carried out at a controlled temperature T2. After the reaction was completed, the reaction solution was poured into purified water, stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I. The synthetic route is shown below:
[0021]
[0022] In a preferred embodiment, the acid-binding agent B mentioned in step 2 is selected from one or a combination of sodium bicarbonate, sodium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine, with sodium carbonate being particularly preferred.
[0023] Preferably, the molar ratio of SM-3 to compound I-1 and the acid-binding agent in step 2 is 1:1.1-1.5:2.6-4.0; particularly preferably 1:1.15:3.2.
[0024] Preferably, the reaction solvent B in step 2 is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile, with N,N-dimethylformamide being particularly preferred.
[0025] Preferably, the reaction temperature T2 in step 2 is 60-100°C, and more preferably 85-90°C.
[0026] The beneficial effects of this invention are:
[0027] This invention provides a novel method for preparing bripiprazole, which has a short synthesis process. It directly uses SM-1 as the starting material, and obtains intermediate I-1 through di-substitution of SM-2. Then, it reacts with SM-3 through a substitution reaction to construct a piperazine ring and obtain the target product bripiprazole I. The product obtained by this process has high yield and purity, and is suitable for industrial production. Detailed Implementation
[0028] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.
[0029] This invention uses HPLC to determine the purity of ibuprofen, and the chromatographic conditions are as follows:
[0030] Column: YMC-Pack ODS-AQ-C 18 (4.6mm×250mm, 5.0μm) or equivalent chromatographic columns;
[0031] Mobile phase: Mobile phase A: 0.02 mol / L potassium dihydrogen phosphate solution (pH adjusted to 2.3 with phosphoric acid); Mobile phase B: acetonitrile;
[0032] Column temperature: 40℃;
[0033] Detection wavelength: 215nm;
[0034] Flow rate: 1.5 mL / min;
[0035] Injection volume: 10 μL;
[0036] The retention time of biriperazole is approximately 30 minutes.
[0037] Table 1 Elution gradient table
[0038]
[0039] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.
[0040] Example 1
[0041] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (34.89 g, 0.22 mol), and triethylamine (35.42 g, 0.35 mol) were added to chloroform (150 mL) and reacted at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 98.6% and a purity of 99.95%.
[0042] Example 2
[0043] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (33.30 g, 0.21 mol), and sodium bicarbonate (29.40 g, 0.35 mol) were added to chloroform (150 mL) and reacted at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 94.3% and a purity of 99.69%.
[0044] Example 3
[0045] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (47.59 g, 0.30 mol), and pyridine (27.685 g, 0.35 mol) were added to chloroform (150 mL) and reacted at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 95.3% and a purity of 99.60%.
[0046] Example 4
[0047] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (34.89 g, 0.22 mol), and triethylamine (25.30 g, 0.25 mol) were added to dichloromethane (150 mL) and reacted at a controlled temperature of 30–35 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 93.9% and a purity of 99.71%.
[0048] Example 5
[0049] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (34.89 g, 0.22 mol), and triethylamine (32.38 g, 0.32 mol) were added to toluene (150 mL) and reacted at a controlled temperature of 65–70 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 94.6% and a purity of 99.65%.
[0050] Example 6
[0051] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (31.72 g, 0.20 mol), and N,N-diisopropylethylamine (29.73 g, 0.23 mol) were added to chloroform (150 mL) and reacted at a controlled temperature of 25–30 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and the organic phase was concentrated to dryness under reduced pressure to obtain intermediate compound I-1, with a yield of 85.6% and a purity of 98.86%.
[0052] Example 7
[0053] Compound 4-aminobenzo[b]thiophene (SM-1, 14.92 g, 0.10 mol), compound SM-2 (50.75 g, 0.32 mol), and N,N-diisopropylethylamine (54.29 g, 0.42 mol) were added to toluene (150 mL) and reacted at a controlled temperature of 70–75 °C. After the reaction was completed, the reaction solution was poured into purified water (1 L), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), and concentrated under reduced pressure to dryness to obtain intermediate compound I-1, with a yield of 87.3% and a purity of 98.22%.
[0054] Preparation of iripepiperazole
[0055] Example 8
[0056] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (31.53 g, 0.115 mol), and sodium carbonate (33.92 g, 0.32 mol) were added to N,N-dimethylformamide (250 mL). The reaction was carried out at a controlled temperature of 85–90 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 97.3% and a purity of 99.98%.
[0057] Example 9
[0058] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (30.16 g, 0.11 mol), and sodium bicarbonate (26.88 g, 0.32 mol) were added to N,N-dimethylformamide (250 mL). The reaction was carried out at a controlled temperature of 85–90 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 93.2% and a purity of 99.70%.
[0059] Example 10
[0060] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (41.13 g, 0.15 mol), and cesium carbonate (104.26 g, 0.32 mol) were added to N,N-dimethylformamide (250 mL). The reaction was carried out at a controlled temperature of 85–90 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 94.1% and a purity of 99.61%.
[0061] Example 11
[0062] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (31.53 g, 0.115 mol), and sodium carbonate (27.56 g, 0.26 mol) were added to N,N-dimethylacetamide (250 mL). The reaction was carried out at a controlled temperature of 60–65 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 93.8% and a purity of 99.75%.
[0063] Example 12
[0064] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (31.53 g, 0.115 mol), and sodium carbonate (42.40 g, 0.40 mol) were added to N-methylpyrrolidone (250 mL). The reaction was carried out at a controlled temperature of 95–100 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 94.2% and a purity of 99.66%.
[0065] Example 13
[0066] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (27.42 g, 0.1 mol), and triethylamine (24.29 g, 0.24 mol) were added to acetonitrile (250 mL) and reacted at a controlled temperature of 55–60 °C. After the reaction was confirmed to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 87.3% and a purity of 98.69%.
[0067] Example 14 (Outside the Upper Limit)
[0068] Compound SM-3 (23.22 g, 0.10 mol), compound I-1 (46.61 g, 0.17 mol), and triethylamine (54.29 g, 0.42 mol) were added to N-methylpyrrolidone (250 mL). The reaction was carried out at a controlled temperature of 100–105 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (2.50 L), stirred to induce crystallization, and then filtered. The resulting solid was dried under reduced pressure to obtain the target compound, birepiperazole I, with a yield of 85.6% and a purity of 97.88%.
Claims
1. A method for preparing biriperazole, characterized in that, The preparation method includes the following steps: Step 1: Add compound SM-1, compound SM-2, and acid-binding agent A to reaction solvent A, and react at temperature T1. After the reaction is completed, pour the reaction solution into purified water, and concentrate the organic phase to dryness under reduced pressure to obtain intermediate compound I-1. Step 2: Add compound SM-3, compound I-1, and acid-binding agent B to reaction solvent B, control the temperature at T2, and after the reaction is completed, pour the reaction solution into purified water, stir to precipitate crystals, filter, and dry the obtained solid under reduced pressure to obtain the target compound burepiperazole I. The reaction route is as follows:
2. The preparation method according to claim 1, characterized in that, The acid-binding agent A mentioned in step 1 is selected from sodium bicarbonate, pyridine, triethylamine, and N,N-diisopropylethylamine.
3. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM-1, compound SM-2, and acid-binding agent in step 1 is 1:2.1-3.0:2.5-4.
0.
4. The preparation method according to claim 1, characterized in that, The reaction solvent A mentioned in step 1 is selected from one or a combination of dichloromethane, chloroform, and toluene.
5. The preparation method according to claim 1, characterized in that, The reaction temperature T1 in step 1 is 30–70°C.
6. The preparation method according to claim 1, characterized in that, The acid-binding agent B mentioned in step 2 is selected from one of sodium bicarbonate, sodium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine.
7. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of SM-3 to compound I-1 and the acid-binding agent is 1:1.1-1.5:2.6-4.
0.
8. The preparation method according to claim 1, characterized in that, The reaction solvent B mentioned in step 2 is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and acetonitrile.
9. The preparation method according to claim 1, characterized in that, The reaction temperature T2 in step 2 is 60–100°C.