Synthesis method of asymmetric amino urea

Abstract

The invention provides a synthesis method of asymmetric amino urea (V), which comprises the following steps: directly activating an amine compound (I) by a phenyl chloroformate compound (II) to obtain a carbamate compound (III), and directly reacting the carbamate compound (III) with an amine compound (IV) to obtain the asymmetric amino urea (V). According to the invention, the compound phenyl chloroformate compound (II) is introduced, two molecules of different amine compounds are activated to directly form asymmetric urea, the process adopts a one-pot method, the steps are relatively short, the operation is simple, and the cost is low. R < 1 > and R < 2 > are respectively and independently C1-C6 alkyl groups, aryl groups and heterocyclic rings; r is hydrogen, C1-C6 alkyl, aryl, heterocyclic ring, halogen or nitryl.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and more particularly to a method for synthesizing asymmetric aminoureas. Background Technology

[0002] Rapamycin signaling pathway inhibitors are selective dual inhibitors of phosphoinositol 3-kinases (PI3Ks) and mTOR. Abnormal activation of this pathway plays a crucial role in various diseases, particularly malignant tumors. In recent years, inhibitors targeting the PI3K / mTOR pathway have shown preliminary efficacy in anti-tumor therapy, with some inhibitors successfully approved and applied clinically, ushering in a new era of precision therapy targeting the PI3K / mTOR pathway. PI3K is classified into three subtypes, with type I PI3K being the most widely studied. Type I PI3K is further divided into IA and IB types. Type IA is most strongly associated with tumor behavior and consists of the p110α, p110β, and p110δ catalytic subunits encoded by the PIK3CA, PIK3CB, and PIK3CD genes, as well as the p85 regulatory subunit. Type IB consists only of the p110γ catalytic subunit encoded by PIK3CG and the p101 and p84 / 87 regulatory subunits. p110α is crucial for PIK3CA mutation-driven tumor growth, p110β is directly associated with tumorigenesis caused by PTEN dysfunction, while p110δ and p110γ are limited to expression in the hematopoietic and immune systems. mTOR consists of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1, located downstream of AKT, drives tumorigenesis by enhancing proto-oncogene transcription and promoting angiogenesis. Its direct downstream substrate, S6 kinase (S6K1), performs metabolic reprogramming by enhancing glycolysis, protein, lipid, and nucleic acid biosynthesis. Another downstream substrate, 4E-BP1, promotes tumor cell proliferation and survival by regulating the transcription initiation complex EIF4f, acting synergistically with CDK4 / 6. mTORC2, located upstream of AKT kinase, regulates cell growth and migration by phosphorylating AKT at the S473 site and modulating cytoskeletal proteins.

[0003] In recent years, research on inhibitors of the rapamycin signaling pathway has increased, with compounds possessing structures showing potential applications in treating diseases and disorders caused by abnormal cell growth. These diseases and disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders.

[0004]

[0005] The difficulty in synthesizing this compound lies in the synthesis of asymmetric aminourea, which easily produces dimer urea, which is difficult to remove, and there are few synthetic methods available.

[0006] Patent CN109641909B discloses the following synthesis method:

[0007]

[0008] The method involves a first step using highly toxic triphosgene to form isocyanates. The procurement and use of triphosgene are subject to regulation and restrictions by public security departments, limiting its application. The second step involves condensation in dichloromethane to synthesize urea, with a yield of only 25.6%.

[0009] The following route is reported in patent AU2004202678 A1:

[0010]

[0011] This route introduces compounds (VII) and (VIII) to prepare an active carbonate compound (IX), which then reacts with an aminothiazole to give a carbamate compound (X). Compound (X) then reacts with a secondary amine to give compound (I). This reaction process is complex, involving a three-step construction of the active reagent (I) followed by its departure in subsequent steps, resulting in poor atom economy. Furthermore, the reaction introduces the odorous compound benzenethiol. The operation is lengthy, complex, and yields poor results.

[0012] To address the issues of complex processes, harsh reaction conditions, and severe pollution in existing technologies, there is an urgent need to develop a simple, safe, mild, high-yield, and environmentally friendly method for the synthesis of asymmetric aminoureas. Summary of the Invention

[0013] To address the shortcomings of existing technologies, this invention provides a one-pot method for synthesizing asymmetric aminoureas, which solves the problems of complex processes and severe pollution in existing technologies.

[0014] This invention provides a method for synthesizing asymmetric aminourea (V). Under alkaline conditions, an urethane ester compound (III), obtained by activating an amine compound (I) with a phenyl chloroformate compound (II), is directly reacted with an amine compound (IV) to obtain the product. The reaction formula is as follows:

[0015]

[0016] R1 and R2 are each independently C1-C6 alkyl, aryl, or heterocyclic; R is hydrogen, C1-C6 alkyl, aryl, heterocyclic, halogen, or nitro.

[0017] This invention also provides a method for synthesizing asymmetric aminourea (V-1), characterized in that, under the action of an alkaline system, a carbamate compound (III-1) obtained by activation of an amine compound (I-1) with a phenyl chloroformate compound (II-1) is directly reacted with an amine compound (IV-1) to obtain the product, as shown in the following reaction formula:

[0018]

[0019] The detailed process for further reaction is as follows: In the reaction solvent, add an amine compound (I), add a base, and then add a phenyl chloroformate compound (II). Maintain the reaction temperature until complete. Then add an amine compound (IV). Increase the temperature and react, take a sample until the reaction is complete, wash with alkaline water, concentrate, dissolve and crystallize to obtain the asymmetric urea compound (V).

[0020] The base used in the reaction is triethylamine, diisopropylethylamine, pyridine, or DBU, with pyridine being the preferred choice.

[0021] The reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, and acetonitrile, with dichloromethane being more preferred.

[0022] The molar ratio of amine compound (I): phenyl chloroformate compound (II): amine compound (IV) is in the range of 1:(1.0~10):(1.0~10), preferably 1:1.1:1.1.

[0023] The reaction temperature after adding the phenyl chloroformate compound is -10℃ to 60℃, preferably 0℃ to 10℃. The reaction temperature after adding another fragment amine compound (IV) is 0℃ to 100℃, preferably 40℃ to 60℃.

[0024] The acid or base used to remove phenolic compounds by adding alkaline water for layering is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, with sodium hydroxide being preferred.

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

[0026] The core of this invention is the introduction of phenyl chloroformate compound II. After activation, two molecules of different amino groups directly form an asymmetric urea. The process adopts a one-pot method, with mild reaction conditions, high yield, short steps, simple operation, high atom economy, and low cost, thus avoiding the use of highly toxic chemicals. Detailed Implementation

[0027] To further understand the present invention, a method for synthesizing asymmetric aminoureas via a one-pot process, provided by the present invention, is described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.

[0028] Example 1: Preparation of Compound III

[0029] Compound I (2.5 g, 1.0 eq) was added to 150 mL of dichloromethane, followed by pyridine (1.6 g, 2 eq). The temperature was controlled at 0-10 °C. Phenyl p-nitrochloroformate (2.2 g, 1.1 eq) was added in portions. The mixture was heated to 20-30 °C and reacted for 3 h. The reaction was completed by TLC (DCM:MeOH = 20:1). The mixture was used directly in the next step without further treatment.

[0030] Example 2: Preparation of compound V

[0031] Compound II (3.4 g 1.1 eq) was added and the mixture was heated to 40 °C and reacted for 16 h. The reaction was basically complete by TLC (DCM:MeOH = 20:1). 50 ml of water was added to the reaction solution and the pH of the solution was adjusted to 9-10 with NaOH. Excess was removed by washing with water to obtain acyl chloride and p-nitrophenol byproducts. The organic layer was concentrated to dryness under reduced pressure at 40 °C. 15 ml of isopropanol was added, and the mixture was crystallized and filtered to obtain 4.15 g of compound V, with a yield of 73%.

[0032] (MeOD-d,400MHz):88.15-8.10(m,2H),7.57-7.55(m,1H),7.49(s,1H),7.48(s ,1H),7.44(s,1H),7.43(s,1H),7.33-7.32(m,2H),6.82-6.80(m,1H),6.60-6. 58(m,1H),4.00(t,4H,J=4.8Hz),3.76(t,4H,J=4.8Hz),3.51(s,1H),3.41-3.3 5(m,2H),2.76(s,6H),2.05-2.01(m,2H),1.61-1.58(m,2H),1.52-1.49(m,2H).

[0033] The method of this invention has the advantages of simple and safe process, mild reaction conditions, high yield and no environmental pollution in the synthesis of substrates.

Claims

1. A method for synthesizing asymmetric aminourea (V), characterized in that, Under the action of an alkaline system, carbamate compound (III), obtained by activation of amine compound (I) by phenyl chloroformate compound (II), is directly reacted with amine compound (IV) to obtain carbamate compound (III). The reaction formula is as follows: R1 and R2 are each independently C1-C6 alkyl, aryl, or heterocyclic; R is hydrogen, C1-C6 alkyl, aryl, heterocyclic, halogen, or nitro.

2. A method for synthesizing an asymmetric aminourea (V-1), characterized in that, In an alkaline system, carbamate compound (III-1), obtained by activation of amine compound (I-1) with phenyl chloroformate compound (II-1), is directly reacted with amine compound (IV-1) to produce carbamate compound (III-1). The reaction formula is as follows: 。 3. A method for synthesizing an asymmetric aminourea (V), characterized in that, In the reaction solvent, amine compound (I) is added, followed by a base, and then phenyl chloroformate compound (II). The reaction is maintained at a constant temperature until complete. Then, amine compound (IV) is added, and the reaction is heated to obtain the final product.

4. The synthesis method according to claim 1, 2 or 3, characterized in that, The base for the reaction is triethylamine, diisopropylethylamine, pyridine, or DBU.

5. The synthesis method according to claim 1, 2 or 3, characterized in that, The reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, or acetonitrile.

6. The synthesis method according to claim 1, 2 or 3, characterized in that, The molar ratio of the amine compound (I): phenyl chloroformate compound (II): amine compound (IV) is in the range of 1:(1.0~10):(1.0~10).

7. The synthesis method according to claim 1, 2 or 3, characterized in that, The reaction temperature after adding phenyl chloroformate compound (II) is -10℃ to 60℃.

8. The synthesis method according to claim 1, 2 or 3, characterized in that, The reaction temperature for adding the amine compound (IV) is 0℃~100℃.

9. The synthesis method according to claim 1, 2 or 3, characterized in that, The acid or base used to remove phenolic compounds by adding alkaline water for stratification is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.

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