Synthesis method of 4-methyl-4, 7-diazaspiro [2.5] octane hydrochloric acid

Abstract

The invention belongs to the field of small molecule synthesis, and particularly relates to a synthesis method of 4-methyl-4, 7-diazaspiro [2.5] octane hydrochloric acid. According to the synthetic route provided by the invention, the target product can be synthesized by only three steps, and the reaction safety and the yield are remarkably improved by optimizing the preparation process of the key intermediate compound 2 and the compound 3 and adopting potassium tert-butoxide and tetraisopropyl titanate to respectively replace dangerous reagents as catalysts. The method is easy and convenient to operate and suitable for industrial production, and an efficient way is provided for synthesis of medical intermediates.

Description

Technical Field

[0001] The present invention belongs to the field of small molecule synthesis, and specifically relates to a method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride. Background Art

[0002] Tert-butyl 4-methyl-4,7-diazaspiro[2.5]octane-7carboxylate, a key intermediate of 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride, plays an important role in the synthesis of antiviral, anticancer, and central nervous system drugs. With the continued expansion of the global pharmaceutical market and the increasing demand for novel drug research and development, the need for efficient, safe, and stable synthesis processes for this target compound is becoming increasingly urgent.

[0003] However, the existing synthesis methods have certain technical defects, which seriously restrict their widespread application and industrial development in the field of medicine. First, in certain key steps of the synthesis process, strong reducing agents are often required. These reagents are extremely active in nature and can easily cause violent reactions. A slight carelessness during operation may cause safety accidents, posing a certain threat to the safety of the operators, and also bringing a burden to the company's production safety management. Secondly, the preparation process of key intermediates faces the problem of unstable yield. Due to the complexity of the multi-step reactions of the existing synthesis routes, the purity of the system is difficult to accurately control, resulting in difficulties in the purification operation of the intermediates, which in turn seriously affects the overall yield of the target compound, making it impossible to meet the stable demand for raw material supply for large-scale production and drug research and development, which directly leads to rising production costs and high drug prices. Furthermore, traditional synthesis routes have many steps and lengthy operation procedures. For example, patent document WO2018 / 145860A1 discloses a synthesis route for 4-methyl-4,7-diazaspiro[2.5]octane, which involves 6 steps of reaction and is relatively complicated. This not only increases the time and labor costs in the production process, but also reduces the utilization rate of production equipment, making it difficult to effectively improve production efficiency.

[0004] Existing technologies have significant deficiencies in safety, yield stability, and ease of operation, making them difficult to adapt to the modern pharmaceutical industry's requirements for efficient, safe, and stable production. Therefore, there is an urgent need to develop a novel synthesis process that can effectively address these issues and achieve the safe, efficient, and stable synthesis of target compounds, enabling successful application in large-scale industrial production. Summary of the Invention

[0005] In order to solve the above technical problems, the present application provides a method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride (CAS: 1152111-72-2), the synthetic route of which is as follows:

[0006] First step reaction:

[0007]

[0008] Second step reaction:

[0009]

[0010] The third step reaction:

[0011]

[0012] The starting material of the synthetic route of the present invention is tert-butyl 3-oxo-1-piperazinecarboxylate, CAS No. 76003-29-7, referred to as Compound 1 in this application, a common commercially available drug.

[0013] The present invention selects tert-butyl 3-oxo-1-piperazinecarboxylate as a starting material, mainly based on its stable chemical properties, not easily deteriorating under normal temperature and pressure, and moderate reactivity, can react efficiently with a variety of reagents without being easily out of control, and lays a good foundation for subsequent steps. In terms of process, the synthetic route using it as a starting point is concise and compact, significantly reduces unnecessary reaction steps, reduces the probability of side reactions and safety risks, and reduces costs. The raw material is extremely compatible with the subsequent reaction steps, does not require complex structural modification or additional protection and deprotection, and the subsequent reaction conditions are mild, do not require extreme temperature and pressure, further reduce equipment requirements and safety risks, improve reaction selectivity and yield, and make the entire process easier to optimize and more suitable for large-scale and industrial production.

[0014] As an implementable example, in the first step reaction, the reaction raw materials include compound 1, a first catalyst, a methylating agent and a first solvent.

[0015] As an implementable case, the first catalyst is an organic base.

[0016] Furthermore, the organic base includes one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or potassium ethoxide.

[0017] Furthermore, the organic base is potassium tert-butoxide.

[0018] In terms of reaction activity and selectivity, potassium tert-butoxide is selected as alkaline catalyst in the first step of the present invention, the methylation reaction of compound 1 can be efficiently promoted, and when potassium tert-butoxide and methylating agent act synergistically, target intermediate compound 2 can be accurately generated, reaction selectivity is better, side reaction is few, and product purity is higher, without complicated and tedious post-processing purification step, effectively saving time and cost. Equally common alkaline catalysts such as sodium hydride, chemical property is extremely active, and common solvents such as water, alcohol can react violently, and may even cause explosive safety accidents, and it is extremely high to operating environment requirements, and it is necessary to carry out under the conditions of strict anhydrous and oxygen-free conditions, and complex operation, equipment requirements are harsh, once improper operation or equipment failure occurs, huge safety risks are brought to production personnel and equipment. In contrast, potassium tert-butoxide is relatively mild and stable. In addition, the catalytic conditions of potassium tert-butoxide are easier to control, and reaction can be carried out at lower temperatures, without extremely high temperature or low temperature, reducing dependence and energy consumption on temperature control equipment.

[0019] As an implementable example, the methylating agent includes one of dimethyl sulfate, dimethyl carbonate or methyl iodide.

[0020] Furthermore, the methylating agent is dimethyl sulfate.

[0021] As an implementable example, the first solvent is an aprotic solvent, including one of dimethyl sulfoxide (DMSO), acetonitrile (CH3CN), dichloromethane (CH2Cl2) or tetrahydrofuran (THF).

[0022] Furthermore, the first solvent is tetrahydrofuran.

[0023] Furthermore, the molar ratio of the compound 1, the first catalyst and the methylating agent is 1:(2-3):(1.2-1.5).

[0024] As an practicable case, in the first step reaction, the reaction temperature is 0-25°C and the reaction time is 1-4h.

[0025] As an implementable case, the crude product compound 2 of the first step reaction can be used as the starting material for the second step reaction after drying and concentration. Before drying and concentration, it needs to be quenched and washed with saturated brine.

[0026] As an implementable example, in the second step reaction, the reaction raw materials include compound 2, Grignard reagent, a second catalyst and a second solvent.

[0027] As an implementable example, the Grignard reagent includes ethylmagnesium bromide.

[0028] As an implementable example, the second catalyst includes one of tetraisopropyl titanate, tetrabutyl titanate or tetraethyl titanate.

[0029] Furthermore, the second catalyst is tetraisopropyl titanate.

[0030] In the second step of the present invention, tetraisopropyl titanate is selected as a catalyst for the Grignard reaction, which can accelerate the Grignard reaction and shorten the reaction time. Tetraisopropyl titanate also has good selectivity, inhibits side reactions, singles the reaction direction, and improves product purity. Under conventional reaction conditions, tetraisopropyl titanate is stable and not prone to side reactions or decomposition. It is highly compatible with the Grignard reagent ethylmagnesium bromide, forming an active intermediate that enhances the catalytic effect, improving reaction yield and atom economy. Furthermore, tetraisopropyl titanate has mild reaction conditions and generally exhibits a good catalytic effect within normal pressure and moderate temperature ranges. This reduces equipment requirements, energy consumption, and side reactions caused by high temperature and high pressure, making the reaction safer and easier to control.

[0031] As an implementable example, the second solvent is an aprotic solvent, including one of dimethyl sulfoxide (DMSO), acetonitrile (CH3CN), dichloromethane (CH2Cl2) or tetrahydrofuran (THF).

[0032] Furthermore, the second solvent is tetrahydrofuran.

[0033] As an implementable example, the molar ratio of the compound 2, the Grignard reagent and the second catalyst is 1:(2-3):(0.5-0.8).

[0034] As an practicable example, the mixing temperature of the compound 2, the Grignard reagent and the second catalyst is -60 to -80°C.

[0035] As an practicable case, the reaction temperature of the second step reaction is 60-80°C, and the reaction time is 1-2h.

[0036] As an implementable case, the crude product compound 3 of the second step reaction is further subjected to column chromatography purification. The eluent for column chromatography purification includes dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (50-100):1.

[0037] Furthermore, the eluent also includes ammonia water in an amount of one thousandth of the total volume of dichloromethane and methanol.

[0038] When the present invention selects dichloromethane and methanol to be compounded as eluent, and adds one thousandth of ammonia, it is possible to provide a weakly alkaline environment, contribute to the acidic impurities in the neutralization system, improve the polarity of the eluent, and make the compound 3 with alkalinity better dissolve and elute. Meanwhile, ammonia can interact with the active sites on the silica gel surface, regulate the surface properties of silica gel, thereby improving separation effect, reducing impurity residues, and improving product purity. In addition, the addition of ammonia also affects the interaction between eluent and silica gel, optimizes the retention time in the elution process, and further improves purification efficiency.

[0039] As an implementable case, in the third step reaction, the reaction raw materials include compound 3, hydrochloric acid and a third solvent.

[0040] As an implementable example, the third solvent includes: one of dimethyl sulfoxide, acetonitrile, dichloromethane, ethyl acetate or tetrahydrofuran.

[0041] Furthermore, the third solvent is ethyl acetate.

[0042] As an implementable case, in the third step reaction, hydrochloric acid and the third solvent ethyl acetate need to be mixed to ensure that the mass molar concentration of hydrochloric acid is 4M, and the volume ratio of compound 3 and hydrochloric acid ethyl acetate is 1:5.

[0043] Furthermore, in the third step, the reaction temperature is 20-30° C. and the reaction time is 5-8 h.

[0044] The reaction mechanism of the present invention is roughly as follows: At the beginning of the reaction, tetraisopropyl titanate reacts with the Grignard reagent ethylmagnesium bromide (EtMgBr). The central titanium atom of tetraisopropyl titanate interacts with the alkyl anion in EtMgBr, undergoing an alkylation reaction to form a dialkyltitanium intermediate (Ti(Oi-Pr)2Et2). The diethyltitanium intermediate then rapidly undergoes a β-H elimination reaction, whereby the hydrogen atoms on the adjacent carbon atoms are eliminated, forming a double bond and generating a titanium heterocyclopropane intermediate. This intermediate has a unique structure and reactivity, acting as an equivalent to a 1,2-dicarbon anion, reacting with the carbonyl group, such as in compound 2, to undergo a dialkylation process, introducing two alkyl groups to the carbon atom of the carbonyl group and the adjacent atom, thereby changing the structure and properties of the carbonyl compound. Another portion of ethylmagnesium bromide adds to the titanium center, initiating the formation of the first carbon-carbon bond, to form an oxytitanium cyclopentane complex. In this step, the alkyl anion in the EtMgBr reacts with the titanium center, forming a coordination bond with the titanium atom and simultaneously promoting the connection of the carbon atom with another carbon atom in the substrate, forming a new carbon-carbon bond. This results in a five-membered ring structure containing titanium and oxygen atoms, namely, the titanium-oxygen cyclopentane complex. The amide functional group in the substrate undergoes an elimination reaction in the form of a magnesium oxide salt, eliminating some small molecules and creating conditions for the formation of a second carbon-carbon bond. During this process, the carbon atom in the molecule again connects with other carbon atoms to form a second carbon-carbon bond, thereby constructing a cyclopropane ring structure. The introduction of a cyclopropane ring may affect the compound's physicochemical properties and biological activity. The resulting titanium-cyclopropane intermediate reacts again with the Grignard reagent (EtMgBr) to undergo alkylation. Here, the alkyl anion in the EtMgBr adds to the appropriate position of the titanium-cyclopropane intermediate, regenerating the diethyl titanium intermediate. Simultaneously, the magnesium salt of the product is generated. Finally, an acidification step converts the magnesium salt of the product into the target compound, completing the deboc protection and yielding the desired compound structure.

[0045] Beneficial effects

[0046] (1) In the first step of the present application, potassium tert-butoxide is used instead of sodium hydride as a catalyst, which avoids safety hazards such as violent gas evolution during the reaction and significantly improves operational safety.

[0047] (2) This application solves the problem of unstable yield of traditional methods by optimizing the synthesis process of key intermediates Compound 2 and Compound 3, with yields reaching 85% and 78% respectively.

[0048] (3) The synthetic route provided in this application does not require ultra-low temperature or high pressure equipment, the reaction conditions are mild, the steps are simplified, and it is more suitable for industrial production.

[0049] (4) The synthetic route provided in the present invention is shorter, which reduces the input of reagents and equipment and lowers the production cost.

[0050] (5) The improved synthesis process of this application reduces side reactions, simplifies the purification of intermediates, and improves the purity of the target compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is the H NMR spectrum of compound 3 in Example 1.

[0052] Figure 2 This is the LCMS spectrum of compound 4 in Example 1. DETAILED DESCRIPTION

[0053] Example 1

[0054] This example provides a method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride, and the synthetic route is as follows:

[0055]

[0056] S1, the reaction formula of the first step is:

[0057]

[0058] Specific experimental steps: 50mmol (10g) of compound 1 (commonly available) was placed in 100mL of tetrahydrofuran, 65mmol (8.2g) of dimethyl sulfate was added under stirring, and then 110mmol (12.4g) of potassium tert-butoxide was added in two batches, with the first batch and the second batch adding the same amount; then the reaction was carried out at 25°C for 2h. After the reaction was completed, water was added to quench the unreacted potassium tert-butoxide; 50mL of ethyl acetate was added and extracted, and the extraction was repeated 3 times. The organic phases were combined and collected, washed with saturated brine, dried and concentrated to obtain 12.5g of compound 2 with a yield of 85%. Compound 2 can be directly used in the second step reaction;

[0059] S2, the reaction formula of the second step reaction is:

[0060]

[0061] Specific experimental steps: 53mmol (10g) of compound 2 was dissolved in 75mL of tetrahydrofuran, cooled to -70°C, and then 106mmol of ethylmagnesium bromide and 29mmol of tetraisopropyl titanate were added and mixed evenly; then the temperature was raised to 70°C and the reaction was carried out for 1h. After the reaction was completed, 5 times the volume of the reaction solution was added for quenching, and then the organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography. The eluents were dichloromethane, methanol and concentrated ammonia water. The elution form was gradient elution. The volume ratio of dichloromethane and methanol was increased from 100:1 to 50:1. Ammonia water accounted for 0.1% of the total volume of the eluent. After purification, 9.8g of compound 3 was obtained, and the product yield was 68%; the nuclear magnetic hydrogen spectrum of compound 3 ( 1 H NMR (400 MHz, DMSO), δ = 3.35-3.23 (m, 2H) (overlapping with DMSO water peak), 3.16 (s, 2H), 2.69 (t, 2H), 2.25 (s, 3H), 1.38 (s, 9H), 0.56 (s, 2H) 0.40 (s, 2H)) Figure 1 As shown;

[0062] S3, the reaction formula of the third step reaction is:

[0063]

[0064] Specific experimental steps: hydrochloric acid and ethyl acetate are mixed to obtain a hydrochloric acid and ethyl acetate mixture, and the molar concentration of hydrochloric acid is ensured to be 4M; 20g of compound 3 is dissolved in 100mL of the hydrochloric acid and ethyl acetate mixture at 5°C, and then stirred at 25°C for 6h. After the reaction is completed, the solid is collected by filtration, and then the solid is washed with 40mL of ethyl acetate and dried at 40°C to constant weight to obtain 4-methyl-4,7-diazaspiro[2.5]octane-7carboxylic acid tert-butyl ester hydrochloride with a yield of 100%, which is recorded as compound 4. The LCMS spectrum of compound 4 is shown as follows: Figure 2 shown.

[0065] Comparative Example 1

[0066] This example provides a synthetic route for 4-methyl-4,7-diazaspiro[2.5]octane (the free form of compound 4 in Example 1) based on patent document WO2018 / 145860A1. The specific reaction formula is as follows:

[0067]

[0068] The route in Comparative Example 1 requires six steps to obtain compound 7A (the free form of compound 4). The reaction yield in Step-4 is low. An overly strong reducing agent during the reduction process can cause the three-membered ring to open, thereby affecting the purification and yield of the product.

[0069] By comparing Example 1 with Comparative Example 1, it can be seen that the synthesis route provided by the present invention has fewer steps, lower cost, shorter cycle, and avoids the use of hazardous chemical reagents. It is suitable for industrial production and provides an efficient route for the synthesis of pharmaceutical intermediates.

Claims

1. A method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride, characterized in that: The synthetic route is as follows: First step reaction: Second step reaction: The third step reaction:

2. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloric acid according to claim 1, wherein In the first step reaction, the reaction raw materials include compound 1, a first catalyst, a methylating agent and a first solvent.

3. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloric acid according to claim 2, characterized in that, The molar ratio of the compound 1, the first catalyst and the methylating agent is 1:(2-3):(1.2-1.5).

4. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloric acid according to claim 2, wherein The first catalyst is an organic base.

5. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloric acid according to claim 4, characterized in that The organic base includes one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or potassium ethoxide.

6. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride according to claim 2, characterized in that, The methylating agent includes one of dimethyl sulfate, dimethyl carbonate or methyl iodide.

7. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride according to claim 1, characterized in that In the second step reaction, the reaction raw materials include compound 2, Grignard reagent, a second catalyst and a second solvent.

8. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride according to claim 7, characterized in that: The molar ratio of the compound 2, the Grignard reagent and the second catalyst is 1:(2-3):(0.5-0.8).

9. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride according to claim 7, characterized in that: The Grignard reagent includes ethylmagnesium bromide.

10. The method for synthesizing 4-methyl-4,7-diazaspiro[2.5]octane hydrochloride according to claim 7, characterized in that: The second catalyst includes one of tetraisopropyl titanate, tetrabutyl titanate or tetraethyl titanate.

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