CN116444485B - Nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea - Google Patents

Abstract

The invention discloses a nonmetal catalytic and column-free chromatographic synthesis method of pyridyl-substituted asymmetric urea, which is a novel nonmetal catalytic and column-free chromatographic serial reaction one-pot synthesis method for synthesizing 2-pyridyl-substituted asymmetric urea, aiming at a series of aromatic amine and aliphatic amine, the yields are close to equivalent conversion, and the method comprises sp ² C、sp ³ C. The electron donating and electron withdrawing groups on the O, S, N atom cyclic secondary amine do not influence the reaction efficiency, and the compatibility of the cyclic secondary amine with different tension and chiral groups substituted on the ring is good, and the cyclic secondary amine is easy to amplify. Provides a simple, efficient and sustainable green synthesis scheme to construct asymmetric ureas with very little waste and very high atomic economy.

Description

Metal-free catalytic, column-free chromatography synthesis method of pyridyl-substituted asymmetric urea

【Technical field】

The invention belongs to the technical field of compound synthesis, and specifically relates to a non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas.

【Background technique】

As an important heterocyclic fragment, N-pyridyl-substituted urea is a common skeleton in the fields of medicine, chemistry, biology, materials and other fields. Among them, the ortho-pyridyl substituted type has excellent anti-tumor, anti-diabetic, neuroprotective, antibacterial, and NASH (non-alcoholic steatohepatitis) activities, and is widely used.

Compound 1 is a dual inhibitor of GSK3/CDK5 and resists the proliferation of lung cells and colon cells (Eur. J. Med. Chem., 2015, 101, 274-287).

Compound 2 is a highly efficient selective inhibitor of ERK and shows tumor regression effect in the BRAFV600E xenograft model (J. Med. Chem., 2016, 59, 6501–6511).

Compound 3, Golvatinib (E7050), is a dual inhibitor of c-Met and VEGFR-2. It anti-tumor angiogenesis through a multi-target strategy and is used for the treatment of head and neck cancer (Cancer Sci., 2015, 106, 201–207). It can also be used as a lead for the development of drugs for hepatitis A virus infection (PLOS Biol., 2019, 17, e3000229).

Compound 4, Roblitinib, was approved by the FDA in 2014 as the first highly selective FGFR4 inhibitor to enter clinical practice (J. Med. Chem., 2020, 63, 12542–12573).

Compound 5, whose structure was further optimized, serves as a potential lead, exhibiting superior kinome selectivity and better pharmacokinetic properties (J. Med. Chem., 2022, 65, 3249–3265).

Compound 6 is a novel glucokinase activator for the treatment of type 2 diabetes (J. Med. Chem., 2014, 57, 8180-8186).

Compound 7, GNF2133, as a highly efficient, selective, orally available DYRK1A inhibitor, can improve symptoms related to type I diabetes (J. Med. Chem., 2020, 63, 2958-2973).

Compounds 1-10:

In the treatment of neurodegenerative diseases, especially for the regulation of Alzheimer's disease, compound 8 has a significant inhibitory effect on human recombinant acetylcholinesterase (hAChE) and glycogen synthase kinase-3α/β, and is a potential Multi-target targeting ligands (Eur. J. Med. Chem., 2019, 168, 58–77).

In the field of anti-inflammatory, compound 9 has good safety and has inhibitory effect on Gram-positive bacteria and respiratory infection pathogens through oral administration or intravenous infusion. Inhibiting the MAP3K kinase ASK1 is an attractive strategy for treating non-alcoholic liver diseases, including steatohepatitis and multiple sclerosis (J. Med. Chem., 2017, 60, 3755–3775).

Compound 10 is an effective and selective small molecule inhibitor, showing stronger apoptosis induction, better G1 cell cycle arresting activity, lower cell IC ₅₀ value, and excellent growth inhibition effect in HepG2 cancer cell line. In GS4997 (Eur. J. Med. Chem., 2020, 195, 112277).

Because of its special hydrogen bonding mode, pyridine urea fragments are also commonly used in a variety of functional composite materials. Pyridyl urea-modified trans-tetrafluoroazobenzene has embedded complementary triple hydrogen bonding units, which can be regulated by light to undergo trans-cis photoisomerization, causing drastic changes in the molecular structure. Subtle stereogenic elements in the linear trans state allow it to selectively fold into the cis form, resulting in globular structures with enhanced chiral optical properties (Angew. Chemie Int. Ed., 2017, 56, 3349–3353). 2-Pyridylurea-modified silica was used as a stationary phase, showing a mixed-mode moderately weak anion exchange capability and pH-dependent surface charge reversal (J. Chromatogr. A, 2018, 1560, 45–54). According to the supramolecular chemistry principle and concept of "key + lock" combining target objects, in order to enhance the selectivity of metal-organic framework materials (MOF) in the adsorption process, 2-pyridyl groups with multiple hydrogen bonding motifs can be introduced Urea is realized, which can be applied not only to MOF, but also to a variety of other mesoporous materials, which can target the recognition of larger and complex molecules and then be used for specific separation, sensors and drug delivery (J.Mater.Chem.A, 2019 , 7, 10379–10388). In oligomers containing 2-pyridyl urea units, the pyridine nitrogen atom and the NH of urea form intramolecular hydrogen bonds, and the terminal carbonyl group and the NH of urea form intermolecular hydrogen bonds. Due to the synergistic effect of hydrogen bonds, it can fold and show strong self-assembly behavior, forming a twisted plane. The carbonyl group of the urea segment faces outwards, while NH tends to inward. This important feature is conducive to NH attracting electron-rich substances. The trimers self-assemble into spiral nanotubes and transport chloride ions efficiently. Using this novel and effective strategy to construct self-assembled biomimetic bodies, electron-rich material transport materials can be prepared (Angew. Chemie Int. Ed., 2021, 60, 10833–10841).

Summary of existing classic synthesis schemes:

In many of the above applications, the synthesis of pyridyl urea and its derivatives is mainly through traditional methods, including isocyanate method, azide method, cross-coupling method of aryl halides, phosgene (or phosgene-based substitutes) method, etc. :

(1) Isocyanate method: The synthesis of asymmetric urea can be achieved by the reaction of isocyanate and pyridine amine, but isocyanate is very reactive and difficult to prepare and store. It usually requires harsh conditions, such as strict anhydrous, oxygen-free, and nitrogen atmosphere. Protection, high technical requirements, complex processes, and reduced operability.

(2) Azide method: The acyl azide compound undergoes Curtius rearrangement to generate an active isocyanate intermediate in situ, and then continues to react with amine to prepare asymmetric urea. The synthesis process is complicated, mainly because inorganic/organic azide itself has dangerous and explosive risks. The synthesis process lacks safety and reliability, and this method is not suitable for large-scale industrial production.

(3) Cross-coupling method of aryl halides: Palladium-catalyzed cross-coupling of aryl halides, dominated by the Buchwald reaction, uses toxic and expensive heavy metal reagents. In recent years, although many research groups around the world have continued to improve it, Improving the catalytic efficiency of complexes generally requires the assistance of organophosphine ligands, and the conventional reaction conditions are rigorous and harsh.

(4) Phosgene (or phosgene-based substitute) method: The condensation of phosgene and amine is a traditional method for synthesizing organic ureas, and it has also been applied in industry. Since the raw material phosgene is a highly toxic substance, it produces highly corrosive and polluting halogen-containing waste, which can easily cause equipment scrapping and serious environmental pollution. In addition, this method is not easy to prepare asymmetric urea. The large-scale utilization of phosgene has obvious shortcomings, and scientific researchers have been working hard to find alternatives, such as phosgene polymers, carbonyl diimidazole, phenyl chloroformate, etc. However, the overall yield of the reaction is usually low and a large amount of waste is produced. At the same time, most of these compounds themselves are derived from phosgene synthesis. Taking comprehensive considerations into account, there are major limitations in using phosgene as raw material or phosgene-based substitutes to prepare asymmetric urea.

Recent new synthesis ideas:

1. Carbon monoxide/carbon dioxide as starting raw materials

In recent years, many novel 2-pyridyl urea synthesis methods have emerged.

The palladium-catalyzed reaction of aryl halides and pyridine amines promoted by aryl bisphosphine ligands can produce urea as a product under relatively mild conditions, while other necessary raw materials, including explosive sodium azide and highly toxic carbon monoxide, will needs more attention (Adv. Synth. Catal., 2018, 3602820–2824).

Using cheap and easily available non-metal selenium as the catalyst and carbon monoxide as the carbonylation reagent, an asymmetric substituted urea can be generated through an oxidative carbonylation reaction, but a higher reaction temperature is required, and the carbon monoxide/oxygen mixed gas has a potential explosion hazard (Chinese Chem. Lett., 2019, 30, 375–378).

The pyrolysis reaction between N-(trimethylsilyl)pyridinamine and carbon dioxide can produce thermodynamically favorable symmetric urea. However, the reaction conditions are strict and harsh, requiring not only high temperature and high pressure, but also extremely high equipment requirements and high cost investment. Very expensive (Angew. Chemie Int. Ed., 2019, 58, 5707–5711).

2. Metal catalysis (palladium, rhodium, copper)

Using chloroform to replace highly toxic carbon monoxide, assisted by organophosphorus ligands, and with the participation of a very small amount of surfactants, asymmetric aryl-substituted pyridyl ureas can be obtained through a mild palladium-catalyzed coupling reaction. Unfortunately, the dangers cannot be avoided. of sodium azide (Adv. Synth. Catal., 2018, 360, 4585–4593).

First prepare a symmetric urea, catalyzed by metal rhodium, and then react with another urea to replace one of the amine fragments on one side to obtain an asymmetric urea. However, this method requires first preparing a symmetric urea and then reacting with another urea. Similarly, The synthesis of the starting material urea still faces difficulties in the traditional scheme, and the atom economy is poor. In addition, both tetrakis(triphenylphosphine)rhodium hydride and organophosphorus ligands need to control harsh anhydrous and oxygen-free environments (Org. Lett., 2021, 23, 9382-9386).

Recently, under the catalysis of cheap copper acetate, through N, O chelated copper six-membered cyclic resonance state cycle, combined with the free radical oxygenation strategy, pyridine urea derivatives are generated at room temperature in an open system in a normal pressure air atmosphere. However, the reaction efficiency is affected by the control of the methyl group in the meta position. The yield of non-methyl-substituted 2-aminopyridine-type starting materials is significantly reduced, which greatly limits the expansion space of this method (Org. Chem. Front., 2022, 9, 1354–1363).

[Content of the invention]

In view of the above deficiencies in the prior art, the present invention provides a non-metal catalyzed, column chromatography-free synthesis method of pyridyl-substituted asymmetric urea, which is a non-metal catalyzed, column chromatography-free series reaction one-pot synthesis method, using For the synthesis of 2-pyridyl-substituted asymmetric urea, the inventor explored a novel solution, using the complex formed in situ between phenyl chloroformate and pyridine to undergo intramolecular rearrangement to obtain phenyl carbamate hydrochloride. The target pyridine urea (for example, urea 13 represented by 13 in the following reaction formula, the same below, in other reaction formulas, for example, 16 represents urea 16) is obtained by one-pot synthesis of the series reaction, and the comprehensive yield is close to quantitative complete conversion.

The object of the present invention is achieved through the following technical solutions:

The non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas includes the following steps:

1) Take a reaction flask with a cap of 5 ml (mL), put in a magnetic stirrer, and mix 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine After (11, IPTA) is dissolved in acetonitrile, slowly add phenyl chloroformate drop by drop with a pipette, without nitrogen protection, and control the temperature below 30°C;

The 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine, acetonitrile, and phenyl chloroformate are in the ratio of 0.1mol:300μL:15.8mg ;

2) Seal the above-mentioned reaction bottle with a lid and stir at room temperature overnight to obtain a clear hydrochloride solution. Add an equal volume of 300 μL of tetrahydrofuran;

3) Amplification reaction: Add N, N-diisopropylethylamine (15.5 mg, 20.9 μL, 1.2 equivalents) and cyclic secondary amine (1.0 equivalents) in sequence, raise the temperature to 50°C, and react for 8 hours. The progress is monitored by TLC. , until it is nearly completely converted into the target product urea;

The N, N-diisopropylethylamine and cyclic secondary amine are in a ratio of 20.9 μL: 0.1 mol;

4) After the amplification reaction described in the above step is completed, use ethyl acetate or chloroform to dissolve the reaction mixture, then use a rotary evaporator to remove the solvent, and then wash twice with water, sodium hydroxide aqueous solution, and anhydrous sodium sulfate. Dry the organic phase and remove the solvent with a rotary evaporator to obtain the pyridyl-substituted asymmetric urea, which can be sent directly to NMR analysis.

In the present invention:

The addition of an equal volume of tetrahydrofuran as described in step 2) is the second part of the solvent that needs to be added to the mixed reaction solution. According to the polarity of different reaction substrates, an equal volume of acetonitrile or dichloroethane can also be used instead of tetrahydrofuran. The yield is basically not affected.

The cyclic secondary amine described in step 3) can be replaced with an aromatic amine or an alicyclic amine, specifically including 1,2,3,4-tetrahydroquinoline, primary amine (-NH ₂ ) and secondary amine (-NH- ) structure of aliphatic amines, alicyclic amines, alcohol amines, aromatic amines, aromatic heterocyclic amines; 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (IPTA) can also be replaced with meta- or para-substituted pyridine-type derivatives.

Based on the above reaction mechanism, specifically, the substrate of the reaction in step 3) is replaced, and a series of aromatic amines or alicyclic amines with structural diversity are used as starting materials instead of the above-mentioned cyclic secondary amines, and the yields are close to equivalent conversions. Cyclic secondary amines containing sp ² C, sp ³ C, O, S, and N atoms mainly include the following structures (urea 16-urea 27):

Similarly, the reaction process is further adapted to meta- and para-substituted pyridine-type derivatives, and the corresponding intermolecular rearrangement series reactions are the main ones, thereby mediating the construction of pyridine urea.

Similarly, given that the above reaction has good applicability to a series of alicyclic amines and aromatic amines (such as 1,2,3,4-tetrahydroquinoline with greater steric hindrance and lower activity), most conversion rates are close to 95% , further, aliphatic amines, alicyclic amines, alcohol amines, aromatic amines, and aromatic heterocyclic amines with primary amine (-NH ₂ ) and secondary amine (-NH-) structures can also be used to obtain the corresponding pyridyl-substituted ureas. .

The above-mentioned non-metal-catalyzed, column-chromatography-free synthesis method of pyridyl-substituted asymmetric ureas provides a simple, efficient, and sustainable green synthesis scheme to construct asymmetric ureas with very little waste and extremely high atom economy.

Regarding the above-mentioned non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric urea, the inventor proposed a reasonable mechanism to evaluate the reaction effect. In the presence of triethylamine, since the nitrogen atom of triethylamine is larger than the nitrogen atom on the pyridine ring, As the exocyclic aromatic nitrogen atom is highly nucleophilic, phenyl chloroformate may first react with the triethylamine nitrogen atom to produce an active ammonium ion intermediate, which then reacts with pyridylamine (IPTA) in a thermodynamic pathway (Path I ) dominates the bimolecular reaction.

In the absence of triethylamine, it is speculated that the reaction is initiated by a complex formed in situ between phenyl chloroformate and pyridine nitrogen atoms. The kinetic pathway (path II) dominates, and then phenyl carbamate hydrochloride is obtained through intramolecular rearrangement. salt; while path II has a lower energy barrier and is the dominant path. Density Functional Theory (DFT) research, DFT confirmed the rationality of this inference:

DFT calculations verify the reaction path to generate compound 2:

The key series reaction is one-pot synthesis to obtain the target product pyridine urea. In order to systematically study its aminolysis mechanism, density functional theory model is used, including the introduction of tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), phenoxycarbonyl (PhCO) ) and other three intermediates with different activation modes, respectively compare their BAC2 (Path Ⅲ, addition-elimination step-by-step pathway, through the zwitterionic intermediate), E1cB path (Path Ⅳ, through the elimination of neutral isocyanate intermediate- Addition mechanism) and concerted mechanism (Path V, the concerted reaction is completed in one step, and the formation of new bonds and the breaking of old bonds occur at the same time).

Path III (BAC2, addition elimination path):

Path IV (isocyanate, elimination of addition path):

Path V (coordination mechanism):

By calculating the energy barrier for the reaction to occur (reaction energy barrier for ammonolysis, kcal/mol):

For Path III, the first step of the addition reaction is the rate-determining step, and the energy barriers for t-Bu, Bn and Ph substituents are 42.7, 38.1 and 33.3 kcal/mol respectively; the reaction energy of the rate-determining step in Path IV The barriers are 48.1, 51.2 and 51.5kcal/mol respectively; the reaction energy barriers of path V are 42.4, 30.1 and 14.9kcal/mol respectively. The reaction energy barriers indicate that path V is the most likely pathway, although cooperative reaction mechanisms are uncommon.

The nitrogen atom in the morpholine molecule of the nucleophile attacks the carbon atom in the carbonyl group of the electrophile, which is a four-membered ring transition state. While the C-N bond is partially generated and the acyloxy bond is partially broken, a hydrogen atom on the NH is transferred to the acyloxy On the oxygen atom of the bond, the electrical neutrality of the transition state is maintained. In general, the BAC2 or E1cB pathway is the dominant pathway in classical theory. The above calculation conclusion is not consistent with this, but is more consistent with the phenomena and results observed in actual reactions (high temperature 85°C, intermediates are not degraded, and the reaction speed is obvious Speed up, 2.5 hours, conversion rate 95.8%).

In order to explore its detailed substrate action mechanism, closely combine and comparatively analyze the experimental data, the inventor used theoretical and computational chemistry methods, and after detailed density functional theory (DFT) research, came to the conclusion:

1. The non-metal catalyzed and column chromatography-free synthesis method of pyridyl-substituted asymmetric urea according to the present invention. The reaction is initiated by the complex generated in situ between phenyl chloroformate and pyridine, and phenyl carbamate is obtained through intramolecular rearrangement. ester hydrochloride, followed by a one-pot synthesis of series reactions to obtain the target product pyridinourea;

2. At the same time, the inventor found that the process proposed in the prior art involves a step-by-step process to obtain an intermediate state of a zwitterion (addition-elimination; Path III), or the classic intermediate state of neutral isocyanate (elimination-addition; Path III) IV), the overall energy barrier of both is too high, making it difficult to realize; and the non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric urea according to the present invention is based on the simultaneous generation of a new bond and the breaking of the old bond. The concerted mechanism (path V) has a more favorable overall energy barrier, and theoretical calculations can provide convincing data and can reasonably explain the regulatory factors associated with mild organic base catalysis; the reaction process described in the present invention It can be further expanded to be suitable for meta- and para-substituted pyridine-type derivatives, and the corresponding intermolecular rearrangement series reactions are the main ones, thereby mediating the construction of pyridine urea.

Compared with the prior art, the present invention has the following advantages:

1. The non-metal catalyzed and column-chromatography-free synthesis method of pyridyl-substituted asymmetric urea according to the present invention is a novel one-pot series reaction method. For a series of aromatic amines and aliphatic amines, the yields are close to those of Quantity conversion, electron-donating and electron-withdrawing groups on cyclic secondary amines containing sp ² C, sp ³ C, O, S, and N atoms do not affect the reaction efficiency.

2. The non-metal catalytic and column chromatography-free synthesis method of pyridyl-substituted asymmetric urea according to the present invention has a variety of solvent combinations, can adapt to starting materials of different polarities, and has a wide range of applications; the catalytic conditions are close to neutral , almost completely converted into the target urea at relatively low temperature, which can effectively suppress or eliminate undesirable side reaction products (such as racemization of chiral centers).

3. The non-metal-catalyzed, column-chromatography-free synthesis method of pyridyl-substituted asymmetric urea according to the present invention has good compatibility with ring systems of different tensions and chiral groups substituted on the ring, and the process flow is easy to scale up. , so it is particularly suitable for the preparation of expensive chiral drugs or corresponding high value-added key intermediates, and is extremely convenient for large-scale industrial application.

[Picture description]

Figure 1 is a diagram illustrating the optimization of the reaction conditions of the non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric urea according to the present invention;

Figure 2 shows the one-pot synthesis principle (cooperative path) of the series reaction of the non-metal catalyzed, column chromatography-free synthesis method of pyridyl-substituted asymmetric urea according to the present invention and the substrate substitution (ortho, meta) reaction in step 3). , para-substituted pyridyl urea).

【Detailed ways】

The specific embodiments of the present invention will be further described below in conjunction with examples.

Example 1:

The non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas includes the following steps:

1) Take a reaction bottle with a cap of 5 ml, put in a magnetic stirrer, 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (IPTA, 20.3 mg, 0.1 mol, 1.0 equivalent) dissolved in acetonitrile (300 μL, 15 times the volume), slowly add phenyl chloroformate (15.8 mg, 12.6 μL, 1.0 equivalent) drop by drop with a pipette. Nitrogen protection is generally not required, and the temperature is controlled at Below 30℃;

2) Cover and seal, stir at room temperature overnight to obtain a clear hydrochloride solution, add an equal volume of tetrahydrofuran (300 μL);

3) Then, add N,N-diisopropylethylamine (15.5 mg, 20.9 μL, 1.2 equivalent) and cyclic secondary amine morpholine (1.0 equivalent) in sequence, raise the temperature to 50°C, and react for 8 hours. The progress is based on TLC Monitoring, usually, 8 hours is close enough to complete conversion to the target product urea;

4) After the amplification reaction (0.1 mmol scale) is completed, the conventional solvent ethyl acetate or chloroform can be used to dissolve the reaction mixture, then use a rotary evaporator to remove the solvent, and then wash twice with an appropriate amount of water and sodium hydroxide aqueous solution. , dry the organic phase with anhydrous sodium sulfate, remove the solvent with a rotary evaporator, and obtain the crude urea, which is directly sent for nuclear magnetic examination and analysis. The results show that the purity is high, and the starting raw materials are almost completely converted quantitatively.

The yield of the target product urea 13 was 97.6%.

Example 2:

The non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas includes the following steps:

1) Take a reaction bottle with a cap of 5 ml, put in a magnetic stirrer, 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (IPTA, 20.3 mg, 0.1 mol, 1.0 equivalent) dissolved in acetonitrile (300 μL, 15 times the volume), slowly add phenyl chloroformate (15.8 mg, 12.6 μL, 1.0 equivalent) drop by drop with a pipette. Nitrogen protection is generally not required, and the temperature is controlled at Below 30℃;

2) Cover and seal, stir at room temperature overnight to obtain a clear hydrochloride solution, add an equal volume of acetonitrile (300 μL);

3) Then, add N,N-diisopropylethylamine (15.5 mg, 20.9 μL, 1.2 equivalent) and cyclic secondary amine morpholine (1.0 equivalent) in sequence, raise the temperature to 50°C, and react for 8 hours. The progress is based on TLC Monitoring, usually, 8 hours is close enough to complete conversion to the target product urea;

4) After the amplification reaction (0.1 mmol scale) is completed, the conventional solvent ethyl acetate or chloroform can be used to dissolve the reaction mixture, then use a rotary evaporator to remove the solvent, and then wash twice with an appropriate amount of water and sodium hydroxide aqueous solution. , dry the organic phase with anhydrous sodium sulfate, remove the solvent with a rotary evaporator, and obtain the crude urea, which is directly sent for nuclear magnetic examination and analysis. The results show that the purity is high, and the starting raw materials are almost completely converted quantitatively.

The yield of the target product urea 13 was 89.8%.

Example 3:

The non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas includes the following steps:

1) Take a reaction bottle with a cap of 5 ml, put in a magnetic stirrer, 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (IPTA, 20.3 mg, 0.1 mol, 1.0 equivalent) dissolved in acetonitrile (300 μL, 15 times the volume), slowly add phenyl chloroformate (15.8 mg, 12.6 μL, 1.0 equivalent) drop by drop with a pipette. Nitrogen protection is generally not required, and the temperature is controlled at Below 30℃;

2) Cover and seal, stir at room temperature overnight to obtain a clear hydrochloride solution, add an equal volume of dichloroethane (300 μL);

3) Then, add N,N-diisopropylethylamine (15.5 mg, 20.9 μL, 1.2 equivalent) and cyclic secondary amine morpholine (1.0 equivalent) in sequence, raise the temperature to 50°C, and react for 8 hours. The progress is based on TLC Monitoring, usually, 8 hours is close enough to complete conversion to the target product urea;

4) After the amplification reaction (0.1 mmol scale) is completed, the conventional solvent ethyl acetate or chloroform can be used to dissolve the reaction mixture, then use a rotary evaporator to remove the solvent, and then wash twice with an appropriate amount of water and sodium hydroxide aqueous solution. , dry the organic phase with anhydrous sodium sulfate, remove the solvent with a rotary evaporator, and obtain the crude urea, which is directly sent for nuclear magnetic examination and analysis. The results show that the purity is high, and the starting raw materials are almost completely converted quantitatively.

The yield of the target product urea 13 was 91.7%.

Example 4-Example 15

Figure 2 shows the one-pot synthesis principle (cooperative path) of the series reaction of the non-metal catalyzed, column-free chromatography synthesis method of pyridyl-substituted asymmetric ureas described in the present application and the substrate substitution (ortho-, meta-) reaction in step 3). , para-substituted pyridyl urea).

Referring to Example 1, after replacing the cyclic secondary amine morpholine in step 3) with other components, the corresponding products urea obtained in high yield are:

Replace the cyclic secondary amine morpholine with other ingredients The corresponding product urea obtained Example 4 Piperidine Urea 16 (yield 91%) Example 5 4-Methoxypiperidine Urea 17 (yield 94.3%) Example 6 N-tert-butoxycarbonyl-piperazine Urea 18 (yield 92.1%) Example 7 Piperazine Urea 19 (yield 90%) Example 8 thiomorpholine Urea 20 (yield 95.5%) Example 9 Pyrrolidine Urea 21 (yield 95.5%) Example 10 1,2,3,4-Tetrahydroquinoline Urea 22 (yield 92.9%) Example 11 1,2,3,4-Tetrahydroisoquinoline Urea 23 (yield 91.3%) Example 12 (R)-2-Methylmorpholine Urea 24 (yield 95.3%) Example 13 (S)-2-Methylmorpholine Urea 25 (yield 97%) Example 14 (R)-3-methylmorpholine Urea 26 (yield 94%) Example 15 (R)-1-N-tert-butoxycarbonyl-2-methylpiperazine Urea 27 (yield 94.4%)

Using the non-metal-catalyzed, column-chromatography-free synthesis method of pyridyl-substituted asymmetric urea of the present application, the yield of the pyridyl-substituted asymmetric urea obtained in Examples 1-15 is 89.8-97.6%.

Comparative ratio:

Green synthetic design at home and abroad:

Comparative example 1:

An economical and practical synthesis scheme of 2-pyridyl-substituted urea without solvent and halogen atoms, using pyridine N-oxide and dialkyl cyanamide as starting materials, which are easy to prepare or commercialize, and carried out under the catalysis of methanesulfonic acid. It has wider substrate applicability, is not sensitive to electron-donating or electron-withdrawing substituents on the pyridine ring, and has excellent yield (63-92%; 19 cases) (GreenChem., 2016, 18, 6630-6636 ).

Comparative example 2:

A synthetic method for pyridyl/quinolyl partially substituted asymmetric ureas was developed. With the help of the re-amination (transamination) reaction of N, N-dimethyl-N'-heteroaryl urea, this scheme does not require metals or bases. Catalyst, suitable for a variety of aryl and alkyl amines (isolated yield 40-96%; more than 50 cases); the reactivity of organic amines is not affected by their own donors or acceptors and different functionalized groups, and is easy to Zoom in to the gram level. Based on experimental data and theoretical calculations, it is deduced that this reaction proceeds through an isocyanate intermediate (Adv. Synth. Catal., 2022, 364, 1295–1304).

Comparative example 3:

A green and environmentally friendly method for preparing various 2-quinolyl-substituted ureas in aqueous phase under mild, non-toxic, non-alkaline and organic solvent conditions. In its scale-up experiment, the product can be quickly collected by simple filtration and ethanol washing, using readily available raw materials, 100% atom economy, high yield and excellent regioselectivity enhance the practicality of this scheme (ACSSustain.Chem. Eng., 2019, 7, 7193–7199).

The prominent limitation of the three similar correlation designs of Comparative Examples 1-3 above is that they are all based on pyridine N-oxidation derivatives as starting materials, and their preparation process requires a more complex enzyme system or a large amount of acidic hydrogen peroxide, and the collection The rate is medium, so it is not conducive to amplification.

At the same time, the preparation of dialkyl cyanamide and carbodiimide-type substrates will produce a lot of waste, and the reaction conditions are also harsh, making it difficult to prepare large quantities using conventional experimental equipment. In addition, under the catalysis of copper sulfate pentahydrate, only trace amounts of 2-isoquinolyl or pyridyl-substituted urea were obtained. It is speculated that the N-oxides corresponding to these two types have low activity.

Comparative example 4:

Recent studies have shown that 2-pyridyl urea derivatives can be obtained by utilizing the tandem reaction of 2-aminopyridinium salts with aromatic amines. This strategy can tolerate a wide range of functional groups and has moderate to good yields. It is speculated that this reaction is a cascade cyclization reaction through intermolecular nucleophilic addition, ring opening and demethylation. However, the unique combination of ortho-pyridinium salts and aromatic amines limits its expansion scope (Tetrahedron Lett., 2019, 60, 150939).

The above are only preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, several improvements and changes can be made without departing from the creative concept of the present invention, and these all belong to the protection of the present invention. scope.

Claims (3)

1. A nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea is characterized in that: the method comprises the following steps:

1) Taking a reaction bottle with a volume of 5 ml and a cover, putting the reaction bottle into a magnetic stirrer, dissolving 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine into acetonitrile, slowly adding phenyl chloroformate dropwise into a liquid transfer gun, and controlling the temperature below 30 ℃ under the protection of no nitrogen gas;

the 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine, acetonitrile and phenyl chloroformate are mixed according to the proportion of 0.1mol:300 mu L:15.8 mg;

2) After the reaction bottle cap with the cover is sealed, stirring overnight at room temperature to obtain a clear hydrochloride solution, and adding 300 mu L of tetrahydrofuran with the same volume;

3) Amplification reaction: sequentially adding N, N-diisopropylethylamine and cyclic secondary amine, heating to 50 ℃, and reacting for 8 hours, wherein the progress is monitored by TLC until the urea is almost completely converted into a target product urea;

the ratio of the N, N-diisopropylethylamine to the cyclic secondary amine is 20.9 mu L to 0.1 mol;

4) After the amplification reaction is finished, ethyl acetate or chloroform is adopted to dissolve the reaction mixture, then a rotary evaporator is used to remove the solvent, water and sodium hydroxide aqueous solution are respectively used for washing 2 times, anhydrous sodium sulfate is used to dry the organic phase, the rotary evaporator is used to remove the solvent, thus obtaining pyridyl substituted asymmetric urea, and nuclear magnetism inspection and analysis are directly carried out.

2. A nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea is characterized in that: the method comprises the following steps:

1) Taking a reaction bottle with a volume of 5 ml and a cover, putting the reaction bottle into a magnetic stirrer, dissolving 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine into acetonitrile, slowly adding phenyl chloroformate dropwise into a liquid transfer gun, and controlling the temperature below 30 ℃ under the protection of no nitrogen gas;

the 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine, acetonitrile and phenyl chloroformate are mixed according to the proportion of 0.1mol:300 mu L:15.8 mg;

2) Sealing the reaction bottle cap with the cover, and stirring overnight at room temperature to obtain a clear hydrochloride solution, and adding 300 mu L of acetonitrile with the same volume;

3) Amplification reaction: sequentially adding N, N-diisopropylethylamine and cyclic secondary amine, heating to 50 ℃, and reacting for 8 hours, wherein the progress is monitored by TLC until the urea is almost completely converted into a target product urea;

the ratio of the N, N-diisopropylethylamine to the cyclic secondary amine is 20.9 mu L to 0.1 mol;

4) After the amplification reaction is finished, ethyl acetate or chloroform is adopted to dissolve the reaction mixture, then a rotary evaporator is used to remove the solvent, water and sodium hydroxide aqueous solution are respectively used for washing 2 times, anhydrous sodium sulfate is used to dry the organic phase, the rotary evaporator is used to remove the solvent, thus obtaining pyridyl substituted asymmetric urea, and nuclear magnetism inspection and analysis are directly carried out.

3. A nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea is characterized in that: the method comprises the following steps:

1) Taking a reaction bottle with a volume of 5 ml and a cover, putting the reaction bottle into a magnetic stirrer, dissolving 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine into acetonitrile, slowly adding phenyl chloroformate dropwise into a liquid transfer gun, and controlling the temperature below 30 ℃ under the protection of no nitrogen gas;

the 6- (4-isopropyl-4H-1, 2, 4-triazole-3-yl) pyridine-2-amine, acetonitrile and phenyl chloroformate are mixed according to the proportion of 0.1mol:300 mu L:15.8 mg;

2) After the reaction bottle cap with the cover is sealed, stirring overnight at room temperature to obtain a clear hydrochloride solution, and adding 300 mu L of dichloroethane with the same volume;

3) Amplification reaction: sequentially adding N, N-diisopropylethylamine and cyclic secondary amine, heating to 50 ℃, and reacting for 8 hours, wherein the progress is monitored by TLC until the urea is almost completely converted into a target product urea;

the ratio of the N, N-diisopropylethylamine to the cyclic secondary amine is 20.9 mu L to 0.1 mol;

4) After the amplification reaction is finished, ethyl acetate or chloroform is adopted to dissolve the reaction mixture, then a rotary evaporator is used to remove the solvent, water and sodium hydroxide aqueous solution are respectively used for washing 2 times, anhydrous sodium sulfate is used to dry the organic phase, the rotary evaporator is used to remove the solvent, thus obtaining pyridyl substituted asymmetric urea, and nuclear magnetism inspection and analysis are directly carried out.