An intermediate compound for synthesizing lumarabepron and a preparation method thereof

Abstract

The application discloses 2-(methylamino) phenylhydrazine and application and a preparation method thereof as a synthetic intermediate of lumefanlum, and belongs to the technical field of pharmaceutical intermediates. The application provides a novel 2-(methylamino) phenylhydrazine intermediate with high purity and without isomer impurities, which is prepared from high-purity N-methyl-ortho-phenylenediamine as a starting material by adopting an in-situ instantaneous diazotization-synchronous reduction coupling process, matching a heavy-metal-free sodium sulfite reduction system and a reduced-pressure rectification purification process. The application avoids the generation of N,N-dimethyl isomer impurities from the source, completely solves the problems of diazonium salt enrichment, heavy metal residue and poor batch stability in the traditional process, and has mild reaction conditions, high production safety, and is suitable for industrial mass production. The intermediate in the application has high purity, good stability and strong reaction specificity, can efficiently construct a lumefanlum tetrahydroindole mother nucleus, significantly improves the purity and yield of a drug substance, is suitable for the strict quality control requirements of high-end lumefanlum drug substances, and has excellent industrial application and patent popularization value.

Description

Technical Field

[0001] This invention belongs to the field of novel intermediates for psychotropic drugs, specifically relating to a novel 2-(methylamino)phenylhydrazine intermediate structure with high purity and free of isomeric impurities, a proprietary preparation process, and its limited application in the synthesis of lumepirozol, suitable for the large-scale safe production of high-end active pharmaceutical ingredients such as lumepirozol and lumepirozol tosylate. Background Technology

[0002] Lumepiride is a first-line atypical antipsychotic drug with definite efficacy against schizophrenia, low side effects, and good patient tolerance, leading to its continuously expanding clinical application. The core pharmacodynamic structure of lumepiroride is a tetracyclic indole nucleus. The directional and high-purity construction of this nucleus is a key technological barrier in the production of the active pharmaceutical ingredient (API), and 2-(methylamino)phenylhydrazine is a necessary key intermediate for achieving Fischer indole cyclization and constructing this tetracyclic nucleus.

[0003] Currently, the conventional route for preparing 2-(methylamino)phenylhydrazine is the o-aminophenylhydrazine methylation process. The process is mature, but it is difficult to adapt to the extreme quality control requirements of high-end active pharmaceutical ingredients. It is very easy to generate N,N-dimethyl isomeric impurities. These isomeric impurities are difficult to separate and remove, and they will directly interfere with the subsequent cyclization reaction of the rumepiride tetracyclic core, leading to a series of problems such as increased side reactions, decreased purity of finished products, and poor batch stability. It cannot meet the stringent quality control standards of high-end active pharmaceutical ingredients.

[0004] Meanwhile, traditional 2-(methylamino)phenylhydrazine preparations often employ a stepwise diazotization process, which leads to the accumulation of diazonium salt intermediates, posing safety hazards such as thermal decomposition and material spillage. This process exhibits poor fault tolerance and high production risks. Furthermore, the frequent use of heavy metal reduction systems can result in heavy metal residues in the intermediates, further hindering the safe production and quality control of high-end rumepiride APIs. Given the stringent requirements for intermediate purity, stability, and batch-to-batch consistency in rumepiride drug synthesis, the industry urgently needs more adaptable high-purity intermediate products and supporting safe and industrialized preparation processes. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies in the synthesis of 2-(methylamino)phenylhydrazine, such as numerous isomeric impurities, low purity, poor stability, insufficient safety of the preparation process, easy generation of heavy metal residues, and incompatibility with the production of high-end rutoperone APIs. This invention provides a high-purity 2-(methylamino)phenylhydrazine intermediate suitable for rutoperone synthesis, along with its preferred preparation method and pharmaceutical applications. This invention utilizes a novel raw material system combined with an in-situ coupled reaction process to avoid the generation of isomeric impurities from the source, resulting in a specialized intermediate with controllable impurities, no heavy metal residues, and excellent stability. Simultaneously, it optimizes the industrial production process, reduces safety risks, and meets the stringent quality control and mass production requirements of high-end APIs.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution.

[0007] This invention provides, on the one hand, a high-purity 2-(methylamino)phenylhydrazine intermediate adapted for the synthesis of rumepiride; on the other hand, it provides a specific industrial preparation process for the intermediate; and finally, it defines the specific pharmaceutical applications of the intermediate in the synthesis of rumepiride and pharmaceutical derivatives.

[0008] I. A novel 2-(methylamino)phenylhydrazine intermediate (see attached figure).

[0009] This invention provides a 2-(methylamino)phenylhydrazine intermediate adapted for the synthesis of lumepirozol, the intermediate having the molecular formula C7H. 11 N3 is a benzene ring ortho-substituted derivative, prepared from high-purity N-methyl-o-phenylenediamine via diazotization, selective reduction, and vacuum distillation. Its molecular structure is fixed and singular, with N-methylamino and hydrazide groups at the ortho positions of the benzene ring. Compared to intermediates prepared by traditional methylation, it completely avoids the generation of N,N-dimethyl isomeric impurities, significantly improving product purity and batch stability. It is specifically suited for the synthesis of high-end lumepirocin API.

[0010] The physicochemical and quality control parameters of this novel intermediate are as follows: it is a colorless to pale yellow transparent oily liquid or a low-temperature crystalline solid; it is readily soluble in ethanol, ethyl acetate, and dichloromethane, soluble in methanol, and slightly soluble in water; it exhibits excellent chemical stability under light-protected and sealed conditions, is not easily oxidized or discolored, and has a long storage period; it can participate in the Fischer indole cyclization reaction efficiently and stably without side reaction interference, and is fully compatible with the high-end quality control standards for rumepiride API.

[0011] II. Optimal preparation process of novel intermediates.

[0012] This invention provides an optimized and industrially suitable preparation process for the aforementioned intermediates, which differs from the traditional o-aminophenylhydrazine methylation synthesis route and can address the industry pain point of excessive isomeric impurities from the source. This invention employs an integrated in-situ instantaneous diazotization-simultaneous reduction coupling technology, which, compared to the traditional stepwise diazotization process, completely eliminates the safety risks of diazonium salt enrichment and decomposition. The reaction conditions are mild, the process has good fault tolerance, and production repeatability is high, making it suitable for industrial-scale production. The specific steps are as follows:

[0013] Step 1: Raw material pretreatment and system preparation.

[0014] The starting material, N-methyl-o-phenylenediamine (purity ≥99.0%, HPLC), was dissolved in dilute hydrochloric acid aqueous solution at a material-to-liquid ratio of 1 g:(8–12) mL. The solution was stirred at room temperature for 15–30 min until completely dissolved, forming a homogeneous and transparent acidic reaction system. A pre-selected amount of sodium sulfite reducing agent was then added to the system, and the mixture was thoroughly stirred to form an in-situ coupled reaction system. Strict control of the purity of the starting material can prevent the introduction of exogenous impurities from the source, ensuring the high purity and batch stability of the target intermediate.

[0015] Step 2: In-situ instantaneous diazotization-synchronous reduction coupled reaction.

[0016] The reaction system was maintained at a safe and mild temperature range of 5–15°C, and an in-situ diazotization reaction was carried out by slowly and uniformly adding an aqueous solution of sodium nitrite. The molar ratio of N-methyl-o-phenylenediamine to sodium nitrite was 1:1.02–1.05, and the precise ratio achieved the directional diazotization of the monoamine. This step adopted a coupled reaction mode of generation and consumption. The diazo intermediate was reduced by the pre-added sodium sulfite in the system instantly after generation, with no risk of diazonium salt enrichment or local accumulation throughout the process. The molar ratio of N-methyl-o-phenylenediamine to sodium sulfite was 1:2.0–2.5, and the coupled reaction was maintained at a constant temperature for 2–3 hours. TLC monitoring showed that the raw materials were completely consumed, and 2-(methylamino)phenylhydrazine hydrochloride was generated directionally.

[0017] Step 3: Alkaline neutralization and extraction to remove impurities.

[0018] After the reaction was completed, a saturated sodium hydroxide solution was slowly added dropwise to the system under low temperature conditions to adjust the pH value of the system to 9.0-10.0, so that the target intermediate could be completely freed and precipitated. After standing and separating the layers, the system was extracted 2-3 times with dichloromethane, with the volume ratio of extraction solvent to reaction liquid being 1:1 each time. All organic phases were combined and washed 1-2 times with saturated brine to remove water-soluble salts, polar impurities and residual acids and bases. The washed organic phases were dried with anhydrous sodium sulfate for 1-2 hours and filtered to remove the desiccant residue, resulting in a clear crude organic liquor.

[0019] Step 4: Refining by vacuum distillation.

[0020] The obtained crude organic liquid was transferred to a vacuum distillation apparatus, and the vacuum degree was controlled at 0.09-0.1 MPa and the pot temperature at 85-95℃. The stable target fraction was collected to completely remove the solvent, trace by-products and high-boiling-point impurities. The product was then stored in a sealed container at low temperature in the dark to obtain a high-purity novel 2-(methylamino)phenylhydrazine intermediate.

[0021] III. Novel intermediates have specific pharmaceutical applications.

[0022] The novel 2-(methylamino)phenylhydrazine intermediate described in this invention is a proprietary core intermediate for the synthesis of lumepirozone, lumepirozone tosylate, and their pharmaceutical derivatives. Compared to traditional methylation intermediates, this novel intermediate is free from isomeric impurities and exhibits high reaction specificity. It can be used to efficiently and with high purity to construct the tetracyclic indole core of lumepirozone via condensation and Fischer indole rearrangement cyclization reactions with piperidinone carbonyl intermediates, making it specifically suitable for the preparation of antipsychotic drugs for the treatment of schizophrenia. Beneficial effects

[0023] Compared with the prior art, the present invention has the following significant advantages: The present invention strictly limits the purity of the starting material N-methyl-o-phenylenediamine to ≥99.0%. Relying on the fixed monomethyl structure and high purity of the raw material, a high-purity intermediate free of N,N-dimethyl isomer impurities can be stably obtained. The introduction of exogenous impurities is strictly controlled from the source, and the product impurities are controllable and the purity is excellent, which is highly compatible with the high-end quality control standards of rumepiride API.

[0024] This invention features a novel in-situ instantaneous diazotization-synchronous reduction coupling process. Compared to traditional stepwise diazotization operations, the diazo intermediates generated can be consumed in a timely manner, completely reducing the risk of diazo salt enrichment and accumulation, and effectively reducing safety hazards such as thermal decomposition and material spillage. The reaction temperature range is wide, energy consumption is reasonable, and the process has a high fault tolerance rate, which greatly improves production safety and batch stability.

[0025] This invention employs a sodium sulfite water-soluble reduction system, without the involvement of heavy metal reagents, thus completely avoiding the problem of heavy metal residues in intermediates; combined with a vacuum distillation deep purification process, the product has fewer by-products, higher purity, better chemical stability and batch consistency, fully meeting the stringent quality control requirements of high-end pharmaceutical raw material intermediates.

[0026] The intermediate structure of this invention is stable and has suitable reactivity, and it is precisely adapted to the Fischer indole synthesis pathway of the rumeperone tetracyclic core, which can effectively improve the yield of subsequent drug substance synthesis and the purity of the finished product. The overall process steps are simple, with low material loss, good repeatability, and safe and controllable, and it has good industrial mass production value and market promotion prospects. Attached Figure Description

[0027] Figure 1 The molecular structure diagram of 2-(methylamino)phenylhydrazine Specific Implementation

[0028] The present invention will be further described in detail below with reference to specific preferred embodiments.

[0029] Example 1: Optimal laboratory preparation process.

[0030] 10 g of N-methyl-o-phenylenediamine (purity ≥99.0%, HPLC), 100 mL of 1 mol / L dilute hydrochloric acid, and 22 g of sodium sulfite were added to a dry reaction vessel and stirred at room temperature for 20 min until completely dissolved. The system was kept at 5–10 °C, and an aqueous solution of 6.5 g of sodium nitrite was added dropwise at a uniform rate. After the addition was complete, the reaction was coupled at this temperature for 2.5 h. TLC monitoring showed complete reaction of the raw materials. No diazonium salt enrichment or safety hazards were observed throughout the process. After the reaction, a saturated sodium hydroxide solution was added dropwise at low temperature to adjust the pH to 9.5. The mixture was allowed to stand and separate into layers. The mixture was extracted three times with 80 mL of dichloromethane each time. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 1.5 h, and filtered to obtain a clear crude liquid. The crude liquid was subjected to vacuum distillation at 0.095 MPa and 90 °C. The stable fraction was collected and stored at low temperature in the dark to obtain 9.4 g of pale yellow transparent oily liquid. The total yield was 79.9%, the product purity was ≥99.0%, and there were no N,N-dimethyl isomer impurities or heavy metal residues.

[0031] Example 2: Industrialized mass production process.

[0032] 50g of N-methyl-o-phenylenediamine (purity ≥99.0%, HPLC), 500mL of 1mol / L dilute hydrochloric acid, and 110g of sodium sulfite were added to an industrial reaction apparatus and stirred at room temperature until fully dissolved. Sodium nitrite aqueous solution was added dropwise at a uniform rate while maintaining the temperature at 8–15℃, and the reaction was carried out at this temperature for 3 hours to achieve a safe reaction mode of in-situ generation and immediate reduction. After the reaction was completed, the pH was adjusted to 9.0–10.0 with alkali, followed by layer extraction, washing, and drying. The target fraction was collected by vacuum distillation at a vacuum degree of 0.09MPa and a vessel temperature of 92℃, yielding 45.2g of a novel 2-(methylamino)phenylhydrazine intermediate, with a total yield of 79.1%. The batch stability was excellent, fully meeting the requirements for safe production and quality control of rumepiride API in industrial applications.

Claims

1. A novel 2-(methylamino)phenylhydrazine intermediate, characterized in that: The intermediate has the molecular formula C7H. 11 N3 is prepared by diazotization and reduction purification of N-methyl-o-phenylenediamine; its molecular structure is a precise substitution structure of N-methylamino and hydrazine group at the ortho position of the benzene ring, without N,N-dimethyl isomer impurities or raw material residues; its appearance is a colorless to pale yellow oily liquid or a low-temperature crystalline solid, and it is a special intermediate for the synthesis of lumepirozoline.

2. A preferred method for preparing the novel 2-(methylamino)phenylhydrazine intermediate according to claim 1, characterized in that, The process includes the following steps: 1) Dissolving N-methyl-o-phenylenediamine in dilute hydrochloric acid aqueous solution, pre-adding sodium sulfite reducing agent, and preparing a homogeneous acidic reaction system; 2) At a mild temperature range of 5-15℃, using an in-situ instantaneous diazotization-synchronous reduction coupled reaction, 2-(methylamino)phenylhydrazine hydrochloride is directionally generated; 3) Neutralizing the solution to pH 9.0-10.0, extracting with dichloromethane, washing with saturated brine, and drying with anhydrous water to remove impurities, to obtain a crude organic liquid; 4) Collecting the target fraction of the crude organic liquid by vacuum distillation to obtain a novel 2-(methylamino)phenylhydrazine intermediate product.

3. The preparation method according to claim 2, characterized in that: The purity of the N-methyl-o-phenylenediamine raw material used is ≥99.0% (HPLC detection); the material-to-liquid ratio in step 1 is 1g:(8~12)mL; in step 2, the molar ratio of N-methyl-o-phenylenediamine to sodium nitrite is 1:1.02~1.05, and the molar ratio of N-methyl-o-phenylenediamine to sodium sulfite is 1:2.0~2.

5.

4. The preparation method according to claim 2, characterized in that: The coupling reaction in step 2 is carried out at a temperature of 5–15°C for 2–3 hours, with no accumulation of diazonium salt intermediates throughout the process.

5. The preparation method according to claim 2, characterized in that: In step 4, the vacuum degree of the reduced pressure distillation is 0.09-0.1 MPa, and the kettle temperature is controlled at 85-95℃.

6. A specific pharmaceutical use of the novel 2-(methylamino)phenylhydrazine intermediate of claim 1, characterized in that: The novel intermediate is specifically used for the preparation of lumepirozol, lumepirozol tosylate, and their pharmaceutical derivatives, for the preparation of antipsychotic drugs for the treatment of schizophrenia.

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