CN116444485A - Nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea - Google Patents
Nonmetallic catalysis and column-free chromatographic synthesis method for pyridyl substituted asymmetric urea Download PDFInfo
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- CN116444485A CN116444485A CN202310325909.3A CN202310325909A CN116444485A CN 116444485 A CN116444485 A CN 116444485A CN 202310325909 A CN202310325909 A CN 202310325909A CN 116444485 A CN116444485 A CN 116444485A
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- Prior art keywords
- urea
- reaction
- amine
- pyridyl
- column
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- 239000004202 carbamide Substances 0.000 title claims abstract description 72
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000001308 synthesis method Methods 0.000 title claims abstract description 19
- 238000006555 catalytic reaction Methods 0.000 title claims description 19
- 125000004076 pyridyl group Chemical group 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- -1 N atom cyclic secondary amine Chemical class 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 11
- MPBBJHFKDHDIRZ-UHFFFAOYSA-N 6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-amine Chemical compound CC(C)N1C=NN=C1C1=CC=CC(N)=N1 MPBBJHFKDHDIRZ-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 6
- 230000004224 protection Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 5
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- 125000003118 aryl group Chemical group 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
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- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- GAOJUAYPDKVFDO-UHFFFAOYSA-N pyridine;urea Chemical group NC(N)=O.C1=CC=NC=C1 GAOJUAYPDKVFDO-UHFFFAOYSA-N 0.000 description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
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- 125000004122 cyclic group Chemical group 0.000 description 5
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
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- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
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- 238000002360 preparation method Methods 0.000 description 4
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- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 3
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- NBTQQBWMWTWDDG-UHFFFAOYSA-N phenyl carbamate;hydrochloride Chemical compound Cl.NC(=O)OC1=CC=CC=C1 NBTQQBWMWTWDDG-UHFFFAOYSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 description 3
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- BHHCXSLGZPPATH-UHFFFAOYSA-N n-trimethylsilylpyridin-2-amine Chemical compound C[Si](C)(C)NC1=CC=CC=N1 BHHCXSLGZPPATH-UHFFFAOYSA-N 0.000 description 1
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- 238000006213 oxygenation reaction Methods 0.000 description 1
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- 238000007699 photoisomerization reaction Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
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- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
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- 229910052711 selenium Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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
[ field of technology ]
The invention belongs to the technical field of compound synthesis, and particularly relates to a nonmetal catalysis and column-free chromatographic synthesis method of pyridyl-substituted asymmetric urea.
[ background Art ]
N-pyridyl substituted urea is taken as an important heterocyclic fragment and is a common framework in the fields of medicine, chemistry, biology, materials and the like. Wherein the ortho-pyridyl substituent has excellent anti-tumor, anti-diabetes, neuroprotection, bacteriostasis and NASH (nonalcoholic steatohepatitis) relieving activities, and has wide application.
Compound 1 is a dual GSK3/CDK5 inhibitor against lung and colon cell proliferation (eur.j. Med. Chem.,2015, 101, 274-287).
Compound 2 is a potent ERK selective inhibitor, exhibiting tumor regression effects in BRAFV600E xenograft models (j.med.chem., 2016, 59, 6501-6511).
Compound 3, golvactinib (E7050), is a dual inhibitor of c-Met and VEGFR-2, anti-tumor angiogenesis by a multi-target strategy, for use in head and neck Cancer treatment (Cancer sci.,2015, 106, 201-207), and can also be used as a lead in the development of hepatitis a virus infection drugs (PLOS biol.,2019, 17, E3000229).
Compound 4, roblitinib was approved by the FDA in 2014 as the first clinically entered highly selective FGFR4 inhibitor (j.med.chem.), 2020, 63, 12542-12573.
Compound 5, which further optimizes structure, exhibits superior kinase group selectivity and better pharmacokinetic properties as a potential lead (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 potent, selective, orally available DYRK1A inhibitor, ameliorates symptoms associated with type I diabetes (j.med.chem., 2020, 63, 2958-2973).
Compounds 1-10:
in the treatment of neurodegenerative diseases, especially for the modulation of alzheimer's disease, compound 8 has a significant inhibitory effect on both human recombinant acetylcholinesterase (hAChE), glycogen synthase kinase-3 a/β, and is a potential multi-target directed ligand (eur.j. Med. Chem.,2019, 168, 58-77).
In the anti-inflammatory field, the compound 9 has good safety and a suppressing effect on gram positive bacteria and respiratory tract infection pathogens through oral administration or intravenous drip. Containment of MAP3K kinase ASK1 is an attractive strategy for the treatment of non-alcoholic liver disease, including steatohepatitis and multiple sclerosis (j.med.chem., 2017, 60, 3755-3775).
Compound 10 is a potent selective small molecule inhibitor exhibiting stronger apoptosis induction, better G1 cell cycle blocking activity, lower cellular IC 50 The value, growth repression in HepG2 cancer cell lines was superior to GS4997 (eur.j. Med. Chem.,2020, 195, 112277).
Because of its own particular mode of hydrogen bonding, the pyridinium urea fragment is also commonly used in a variety of functional composites. The pyridine urea modified trans-tetrafluoroazobenzene has an embedded complementary triple hydrogen bond unit, and trans-cis photoisomerization can occur through light regulation, so that the molecular structure is severely changed. The fine steric causative element in the linear trans state causes it to selectively fold into cis, resulting in a spherical structure with enhanced chiral optical properties (angelw.chemie int.ed.,2017, 56, 3349-3353). 2-pyridylurea modified silica as stationary phase shows a mixed mode moderately weak anion exchange capacity and pH dependent surface charge inversion (j. Chromatogr a,2018, 1560, 45-54). According to the supermolecular chemistry principle and concept of "key+lock" binding to target objects, in order to enhance their selectivity in metal-organic framework Material (MOF) adsorption schemes, this can be achieved by introducing 2-pyridylurea with multiple hydrogen bonding motifs, which can be applied not only to MOFs but also to other various mesoporous materials, which can specifically recognize larger and complex molecules for specific separations, sensors and drug delivery (j.mater.chem.a, 2019,7, 10379-10388). Oligomers containing 2-pyridine urea units, pyridine nitrogen atoms and urea NH form intramolecular hydrogen bonds, and terminal carbonyl groups and urea NH form intermolecular hydrogen bonds. Due to the synergistic effect of hydrogen bonds, the product can fold and show strong self-assembly behavior, a distorted plane is generated, the carbonyl of the urea segment faces outwards, and NH tends to be inwards, and the important characteristic is favorable for attracting electron-rich substances by NH. The trimer can be self-assembled into a spiral nano tube and can efficiently transport chloride ions. By constructing a self-assembled biomimetic using this novel and effective strategy, electron rich substance transport materials (angelw. Chemie int. Ed.,2021, 60, 10833-10841) can be prepared.
Summary of existing classical synthesis schemes:
among the above applications, the synthesis of pyridine urea and its derivatives is mainly carried out by conventional methods including isocyanate method, azide method, aryl halide cross-coupling method, phosgene (or phosgene-based substitute) method, etc.:
(1) Isocyanate process: the synthesis of the asymmetric urea can be realized by adopting the reaction of isocyanate and pyridine amine, but the isocyanate has very high activity, is difficult to prepare and store per se, and generally requires more severe conditions, such as strict anhydrous, anaerobic and nitrogen atmosphere protection, has high technical requirements and complex flow, and reduces operability.
(2) Azide method: the acyl azide undergoes Curtius rearrangement to generate active isocyanate intermediate in situ, and then the acyl azide reacts with amine continuously to prepare the asymmetric urea. The synthesis process is complex, and the inorganic/organic azide is dangerous and explosive. The safety and reliability of the synthesis process are both lacking, and the method is not suitable for large-scale industrial production.
(3) Cross-coupling of aryl halides: palladium catalyzed aryl halide cross coupling with Buchwald reaction as the dominant, using toxic and expensive heavy metal reagents, although many research groups around the world have been continuously improving in recent years, in order to improve the catalytic efficiency of the complex, the assistance of organic phosphine ligands is generally required, and the conventional reaction conditions are strict and harsh.
(4) Phosgene (or phosgene-based substitute) process: the use of phosgene and amine condensation is a conventional method for the synthesis of organic ureas, and has also been used industrially. Because the raw material phosgene is a highly toxic substance, halogen-containing waste with strong corrosiveness and pollution is generated, and equipment scrapping and serious environmental pollution are easily caused. In addition, the process is not prone to the preparation of asymmetric ureas. The large-scale utilization of phosgene has obvious defects, and researchers have been struggling to find alternatives to phosgene polymers, carbonyl diimidazole, phenyl chloroformate and the like. But the overall yield of the reaction is generally low and a large amount of waste is produced. Meanwhile, most of the compounds are derived from phosgene synthesis, and the preparation of asymmetric urea by using phosgene as a raw material or a substitute based on phosgene has great limitation in comprehensive consideration.
New synthetic ideas in recent times:
1. carbon monoxide/carbon dioxide as starting material
In recent years, more novel methods for synthesizing 2-pyridylurea have also emerged.
The palladium-catalyzed aryl halide promoted by the aryl biphosphine ligand reacts with the pyridinamine to give the product urea under milder conditions, while other necessary raw materials, including explosive sodium azide, highly toxic carbon monoxide, require much attention during the reaction process (adv. Synth. Catalyst., 2018, 3602820-2824).
The asymmetric substituted urea can be produced by oxidative carbonylation reaction using inexpensive and readily available nonmetallic selenium as a catalyst and carbon monoxide as a carbonylation reagent, but higher reaction temperatures are required and the carbon monoxide/oxygen mixture is potentially explosive (Chinese chem.
The pyrolysis reaction of N- (trimethylsilyl) pyridinamine with carbon dioxide can give thermodynamically favourable symmetrical urea, however, the reaction conditions are strict and demanding, not only high temperature and pressure are required, but also very high equipment requirements, and the cost input is also very expensive (angel. Chemie int. Ed.,2019, 58, 5707-5711).
2. Metal catalysis (palladium, rhodium, copper)
Chloroform is used to replace highly toxic carbon monoxide, organophosphorus ligand is used for assisting, a very small amount of surfactant is used for participating, and the palladium catalyzed mild coupling reaction can obtain asymmetric aryl substituted pyridine urea, unfortunately, dangerous sodium azide (adv. Synth. Catalyst., 2018, 360, 4585-4593) can not be avoided yet.
Firstly preparing symmetrical urea, then reacting with another urea to replace one side amine fragment under the catalysis of rhodium metal to obtain the asymmetrical urea, but the method needs to prepare symmetrical urea firstly and then reacting with the other urea, and the synthesis of the starting material urea still faces the problems in the traditional scheme and has poor atom economy. In addition, both the tetrakis (triphenylphosphine) rhodium hydride and the organophosphorus ligands require a more demanding anhydrous, anaerobic environment to be controlled (org. Lett.,2021, 23, 9382-9386).
Recently, a pyridine urea derivative is generated at room temperature in an open system atmosphere at normal pressure by using N, O chelated copper six-membered ring resonance state circulation and combining a free radical oxygenation strategy under the catalysis of cheap copper acetate, but the reaction efficiency is influenced by methyl regulation of meta-position, the yield of a non-methyl substituted 2-aminopyridine type initiator is obviously reduced, and the expansion space of the method is greatly limited (org.chem.front., 2022,9, 1354-1363).
[ invention ]
Aiming at the defects of the prior art, the invention provides a nonmetal catalytic and column-free chromatographic synthesis method of pyridyl-substituted asymmetric urea, which is a one-pot synthesis method of nonmetal catalytic and column-free chromatographic serial reaction, and is used for synthesizing 2-pyridyl-substituted asymmetric urea, the inventor explores a novel solution idea, utilizes a complex generated in situ by phenyl chloroformate and pyridine to carry out intramolecular rearrangement to obtain phenyl carbamate hydrochloride, and carries out subsequent serial reaction and one-pot synthesis to obtain target pyridine urea (for example, urea 13 shown in the following reaction formula 13, and in the following other reaction formulas, for example, urea 16 is shown in the following reaction formula), and the comprehensive yield is close to quantitative complete conversion.
The aim of the invention is achieved by the following technical scheme:
the nonmetallic catalysis and column-free chromatographic synthesis method of the pyridyl substituted asymmetric urea comprises the following steps:
1) Taking a reaction bottle with a cover and a volume of 5 milliliters (mL), putting the reaction bottle into a magnetic stirrer, dissolving 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine-2-amine (11, IPTA) in acetonitrile, slowly adding phenyl chloroformate dropwise into a liquid transfer gun, and controlling the temperature below 30 ℃ under the protection of no nitrogen;
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: n, N-diisopropylethylamine (15.5 mg, 20.9. Mu.L, 1.2 eq.) and cyclic secondary amine (1.0 eq.) were added sequentially, warmed to 50℃and reacted for 8 hours, the progress of which was monitored by TLC until near complete conversion to the 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.
In the invention, the following components are added:
the step 2) of adding the tetrahydrofuran with the same volume is to add a second part of solvent to the mixed reaction liquid, and according to the polarities of different reaction substrates, the tetrahydrofuran can be replaced by acetonitrile or dichloroethane with the same volume, so that the yield is not affected basically.
The cyclic secondary amine described in step 3) may be replaced by an aromatic or alicyclic amine, specifically including 1,2,3, 4-tetrahydroquinoline, having a primary amine (-NH) 2 ) And aliphatic amines, alicyclic amines, alcohol amines, aromatic heterocyclic amines of secondary amine (-NH-) structure; 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (IPTA) may also be replaced with meta-and para-substituted pyridine-type derivatives.
Based on the above reaction mechanism, specifically, the substrate reacted in the step 3) is replaced, a series of aromatic amine or alicyclic amine with structural diversity is used as a starting material to replace the cyclic secondary amine, the yield is nearly equivalent to conversion, and sp is contained 2 C、sp 3 C. A cyclic secondary amine of O, S, N atoms, consisting essentially of the following structure (urea 16-urea 27):
similarly, the reaction process further replaces the pyridine derivatives suitable for meta-position and para-position substitution, the corresponding intermolecular rearrangement tandem reaction is mainly carried out, and the construction of pyridine urea is mediated.
Also, in view of the good applicability of the above reaction to a range of alicyclic and aromatic amines (e.g., 1,2,3, 4-tetrahydroquinoline which is relatively bulky and has relatively low activity), most of the conversion rates are close to 95%, and further, primary amines (-NH) 2 ) And aliphatic amines, alicyclic amines, alcohol amines, aromatic amines and aromatic heterocyclic amines of secondary amine (-NH-) structure can likewise be used to obtain the corresponding pyridyl substituted ureas.
The nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea provides a simple, efficient and sustainable green synthesis scheme, and the asymmetric urea is constructed with little waste and extremely high atom economy.
Aiming at the nonmetal catalysis and column-free chromatography synthesis method of the pyridyl-substituted asymmetric urea, the inventor provides a reasonable mechanism to evaluate the reaction effect, and in the presence of triethylamine, because the nitrogen atom of the triethylamine is more nucleophilic than the nitrogen atom of the pyridine ring and the aromatic nitrogen atom outside the pyridine ring, phenyl chloroformate can react with the nitrogen atom of the triethylamine to generate an active ammonium ion intermediate, and the intermediate reacts with the pyridine amine (IPTA) to generate bimolecular reaction with a dominant thermodynamic path (path I).
In the absence of triethylamine, the reaction is supposed to be initiated by a complex generated in situ by phenyl chloroformate and pyridine nitrogen, belonging to the dominant kinetic pathway (pathway II), and then phenyl carbamate hydrochloride is obtained by intramolecular rearrangement; while path II has a lower energy barrier, the dominant approach. Density functional theory (Density Functional Theory, DFT) study, DFT confirmed the rationality of this inference:
DFT calculations verify the reaction pathway leading to compound 2:
the key serial reaction is synthesized in one pot to obtain the target product pyridine urea, the ammonolysis mechanism of the target product pyridine urea is researched systematically, 3 intermediates of different activation modes such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and phenoxycarbonyl (PhCO) are introduced, BAC2 (path III, addition-elimination stepwise approach, through zwitterionic intermediate), E1cB path (path IV, through elimination-addition mechanism of neutral isocyanate intermediate) and synergistic (localized) mechanism (path V, the synergistic reaction is completed in one step, and new bond generation and old bond fracture are concurrent) are respectively compared.
Path III (BAC 2, addition elimination path):
route IV (isocyanate, elimination of addition route):
path V (coordination mechanism):
by calculating the energy barrier (kcal/mol) at which the reaction occurs:
for pathway III, the first addition reaction is a step at a rate of 42.7, 38.1 and 33.3kcal/mol for the t-Bu, bn and Ph substituents, respectively; the reaction energy barriers of the step of determining speed in the path IV are 48.1, 51.2 and 51.5kcal/mol respectively; the reaction energy barriers of pathway V were 42.4, 30.1 and 14.9kcal/mol, respectively. The reaction energy barrier suggests that pathway V is the most likely pathway, although the synergistic reaction mechanism is not common.
The nitrogen atom in the nucleophilic reagent morpholine molecule attacks the carbon atom in the electrophilic reagent carbonyl, and is in a four-ring transition state, and one hydrogen atom on NH is transferred to the oxygen atom of the acyloxy bond while the C-N bond part is generated and the acyloxy bond part is broken, so that the electroneutrality of the transition state is maintained. In general, the BAC2 or E1cB pathway is the dominant pathway in classical theory, and the above calculation conclusion is not consistent with this, but more consistent with the phenomena and results observed in practical reactions (high temperature 85 ℃, intermediate does not degrade, reaction speed is obviously accelerated, 2.5 hours, conversion rate is 95.8%).
To explore its detailed substrate mechanism of action, closely combine and compare analytical experimental data, the inventors applied theoretical and computational chemistry methods, and studied by detailed density functional theory (Density Functional Theory, DFT) to draw conclusions:
1. according to the nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea, the reaction is initiated by a complex generated in situ by phenyl chloroformate and pyridine, phenyl carbamate hydrochloride is obtained through intramolecular rearrangement, and the target product pyridine urea is obtained through one-pot synthesis of subsequent tandem reaction;
2. meanwhile, the inventor finds that the process (addition-elimination; path III) for obtaining the zwitterionic intermediate state or the classical intermediate state (elimination-addition; path IV) of the neutral isocyanate, which is proposed in the prior art and involves a stepwise process, is difficult to realize due to the fact that the whole energy barrier is too high; according to the nonmetal catalysis and column-free chromatography synthesis method of the pyridyl-substituted asymmetric urea, according to a synergistic (condensed) mechanism (path V) of simultaneous occurrence of new bond generation and old bond breakage, the method has more favorable integral energy barrier, theoretical calculation can provide convincing data, and can reasonably explain regulatory factors associated with mild organic base catalysis; the reaction process can be further developed and applicable to meta-position and para-position substituted pyridine derivatives, and the corresponding intermolecular rearrangement tandem reaction is mainly carried out, so that the construction of pyridine urea is mediated.
Compared with the prior art, the invention has the following advantages:
1. the nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea is a novel one-pot method for series reaction, and aiming at a series of aromatic amine and aliphatic amine, the yield is close to equivalent conversion and 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 affect the reaction efficiency.
2. The nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea has a plurality of combined solvents, can adapt to starting materials with different polarities, and has wide application range; the catalytic condition is close to neutral, and the urea is almost completely converted into target urea at relatively low temperature, so that adverse side reaction products (such as racemization of chiral centers) can be effectively inhibited or eliminated.
3. The nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea has good compatibility to ring systems with different tensions and chiral groups substituted on the rings, and the process flow is easy to amplify, so that the method is particularly suitable for preparing chiral medicines with high price or key intermediates with corresponding high added value, and is extremely convenient for large-scale industrialized application.
[ description of the drawings ]
FIG. 1 is a diagram of the optimization of reaction conditions for a nonmetallic catalyzed, column-free chromatographic synthetic method of a pyridyl-substituted asymmetric urea of the present invention;
FIG. 2 is a diagram of the principle of tandem reaction one-pot synthesis (synergistic path) of the nonmetallic catalyzed, column-free chromatographic synthesis method of the pyridyl-substituted asymmetric urea and the substrate substitution (ortho-, meta-, para-substituted pyridine urea) of the reaction of step 3) according to the present invention.
[ detailed description ] of the invention
The following describes the invention in more detail with reference to examples.
Example 1:
the nonmetallic catalysis and column-free chromatographic synthesis method of the pyridyl substituted asymmetric urea comprises the following steps:
1) After taking a reaction bottle with a cover and a volume of 5 ml, putting the reaction bottle into a magnetic stirrer, and dissolving 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (IPTA, 20.3mg,0.1mol,1.0 equivalent) in acetonitrile (300 mu L,15 times the volume), slowly adding phenyl chloroformate (15.8 mg,12.6 mu L,1.0 equivalent) dropwise into a pipette without nitrogen protection, wherein the temperature is controlled below 30 ℃;
2) After sealing, stirring overnight at room temperature to give a clear hydrochloride solution, and adding an equal volume of tetrahydrofuran (300 μl);
3) Then, N-diisopropylethylamine (15.5 mg,20.9 μl,1.2 eq.) and cyclic secondary amine morpholine (1.0 eq.) were added sequentially, warmed to 50 ℃ and reacted for 8 hours, the progress of which was monitored by TLC, typically 8 hours sufficient to nearly completely convert to the target product urea;
4) After the amplification reaction (0.1 mmol scale) is completed, the reaction mixture can be dissolved by using a conventional solvent of ethyl acetate or chloroform, then the solvent is removed by using a rotary evaporator, the organic phase is dried by using anhydrous sodium sulfate for 2 times by using a proper amount of water and a proper amount of sodium hydroxide aqueous solution respectively, the solvent is removed by using the rotary evaporator, crude urea is obtained, the crude urea is directly sent to nuclear magnetism inspection and analysis, and the result shows that the purity is high, and the initial raw material is nearly quantitatively and completely converted.
The yield of the urea 13 as the target product was 97.6%.
Example 2:
the nonmetallic catalysis and column-free chromatographic synthesis method of the pyridyl substituted asymmetric urea comprises the following steps:
1) After taking a reaction bottle with a cover and a volume of 5 ml, putting the reaction bottle into a magnetic stirrer, and dissolving 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (IPTA, 20.3mg,0.1mol,1.0 equivalent) in acetonitrile (300 mu L,15 times the volume), slowly adding phenyl chloroformate (15.8 mg,12.6 mu L,1.0 equivalent) dropwise into a pipette without nitrogen protection, wherein the temperature is controlled below 30 ℃;
2) After sealing, stirring overnight at room temperature to give a clear hydrochloride solution, and adding an equal volume of acetonitrile (300 μl);
3) Then, N-diisopropylethylamine (15.5 mg,20.9 μl,1.2 eq.) and cyclic secondary amine morpholine (1.0 eq.) were added sequentially, warmed to 50 ℃ and reacted for 8 hours, the progress of which was monitored by TLC, typically 8 hours sufficient to nearly completely convert to the target product urea;
4) After the amplification reaction (0.1 mmol scale) is completed, the reaction mixture can be dissolved by using a conventional solvent of ethyl acetate or chloroform, then the solvent is removed by using a rotary evaporator, the organic phase is dried by using anhydrous sodium sulfate for 2 times by using a proper amount of water and a proper amount of sodium hydroxide aqueous solution respectively, the solvent is removed by using the rotary evaporator, crude urea is obtained, the crude urea is directly sent to nuclear magnetism inspection and analysis, and the result shows that the purity is high, and the initial raw material is nearly quantitatively and completely converted.
The yield of the urea 13 as the target product was 89.8%.
Example 3:
the nonmetallic catalysis and column-free chromatographic synthesis method of the pyridyl substituted asymmetric urea comprises the following steps:
1) After taking a reaction bottle with a cover and a volume of 5 ml, putting the reaction bottle into a magnetic stirrer, and dissolving 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (IPTA, 20.3mg,0.1mol,1.0 equivalent) in acetonitrile (300 mu L,15 times the volume), slowly adding phenyl chloroformate (15.8 mg,12.6 mu L,1.0 equivalent) dropwise into a pipette without nitrogen protection, wherein the temperature is controlled below 30 ℃;
2) After sealing, stirring overnight at room temperature to give a clear hydrochloride solution, and adding an equal volume of dichloroethane (300 μl);
3) Then, N-diisopropylethylamine (15.5 mg,20.9 μl,1.2 eq.) and cyclic secondary amine morpholine (1.0 eq.) were added sequentially, warmed to 50 ℃ and reacted for 8 hours, the progress of which was monitored by TLC, typically 8 hours sufficient to nearly completely convert to the target product urea;
4) After the amplification reaction (0.1 mmol scale) is completed, the reaction mixture can be dissolved by using a conventional solvent of ethyl acetate or chloroform, then the solvent is removed by using a rotary evaporator, the organic phase is dried by using anhydrous sodium sulfate for 2 times by using a proper amount of water and a proper amount of sodium hydroxide aqueous solution respectively, the solvent is removed by using the rotary evaporator, crude urea is obtained, the crude urea is directly sent to nuclear magnetism inspection and analysis, and the result shows that the purity is high, and the initial raw material is nearly quantitatively and completely converted.
The yield of the urea 13 as the target product was 91.7%.
Example 4-example 15
FIG. 2 is a schematic representation of the principle of tandem reaction one-pot synthesis (synergistic path) of the nonmetallic catalyzed, column-free chromatographic synthesis of pyridyl-substituted asymmetric ureas and the substrate substitution (ortho-, meta-, para-substituted pyridinureas) of step 3) reactions described herein.
Referring to example 1, after substituting the cyclic secondary amine morpholine in step 3) with other components, the corresponding product urea obtained in high yield was respectively:
substitution of cyclic secondary amine morpholines with other ingredients | The corresponding product urea is obtained | |
Example 4 | Piperidine compounds | Urea 16 (yield 91%) |
Example 5 | 4-methoxypiperidine | Urea 17 (yield 94.3%) |
Example 6 | N-Boc-piperazine | Urea 18 (yield 92.1%) |
Example 7 | Piperazine (PPA) | Urea 19 (yield 90%) |
Example 8 | Thiomorpholine | Urea 20 (yield 95.5%) |
Example 9 | Pyrrolidine compounds | 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-Boc-2-methylpiperazine | Urea 27 (yield 94.4%) |
By adopting the nonmetal catalysis and column chromatography-free synthesis method of the pyridyl-substituted asymmetric urea, the yield of the pyridyl-substituted asymmetric urea obtained in the examples 1-15 is 89.8-97.6%.
Comparative example:
and (3) green synthesis design at home and abroad:
comparative example 1:
the economical and practical 2-pyridyl substituted urea synthesis scheme without solvent and halogen atom takes pyridine N-oxide and dialkyl cyanamide which are easy to prepare or commercialize as starting materials, is catalyzed by methane sulfonic acid, has wider substrate applicability, is insensitive to electron donating and electron withdrawing substituents on a pyridine ring, and has better yield (63-92%; 19 cases) (GreenChem., 2016, 18, 6630-6636).
Comparative example 2:
synthetic methods for pyridinyl/quinolinyl partially substituted asymmetric ureas were developed, which are applicable to a wide variety of aryl and alkylamines without metal, base catalysts by means of the re-amination (transamination) of N, N-dimethyl-N' -heteroaryl urea (isolated yields 40-96%; more than 50); the reactivity of organic amines is not affected by its own donor or acceptor and by different functionalized groups, and is easily amplified to the gram scale. From experimental data, this reaction was deduced by combining theoretical calculations through isocyanate intermediates (adv. Synth. Catalyst., 2022, 364, 1295-1304).
Comparative example 3:
an environment-friendly method for preparing various 2-quinolyl substituted ureas by aqueous phase is carried out under the conditions of mild, non-toxic, non-alkaline and organic solvent. In its scale-up experiments, the product can be collected rapidly by simple filtration and ethanol washing, using readily available starting materials, with 100% atomic economy, high yield and excellent regioselectivity enhancing the utility of the protocol (ACS sustein. Chem. Eng.,2019,7, 7193-7199).
The three similar related designs of the above comparative examples 1 to 3 are all based on pyridine N-oxide derivatives as starting materials, and require a relatively complex enzyme system in the preparation process or a large amount of acidic hydrogen peroxide, and have moderate yields, thus being disadvantageous for scale-up.
Meanwhile, more waste is generated in the preparation of the dialkyl cyanamide and the carbodiimide type substrate, and the reaction conditions are also harsh, so that the dialkyl cyanamide and the carbodiimide type substrate are not easy to prepare in a large quantity by using conventional experimental equipment. Furthermore, copper sulfate pentahydrate catalyzed only trace amounts of 2-isoquinolinyl or pyridyl substituted urea were obtained, presumably with lower activity for both types of corresponding N-oxides.
Comparative example 4:
recent studies have shown that 2-pyridylurea derivatives can be obtained using a tandem reaction of a 2-aminopyridine salt with an aromatic amine, which strategy can tolerate a wide range of functional groups with moderate to good yields. The reaction is presumed to be a cascade cyclization reaction via intermolecular nucleophilic addition, ring opening, and demethylation pathways. However, the unique combination of ortho-pyridinium salts and aromatic amines limits its scope of expansion (Tetrahedron lett.,2019, 60, 150939).
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and changes can be made by those skilled in the art without departing from the inventive concept herein.
Claims (4)
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. The nonmetallic catalyzed, column-free chromatographic synthetic method of pyridyl-substituted asymmetric urea according to claim 1, characterized in that: and 2) adding the tetrahydrofuran with the same volume into the mixed reaction solution, wherein the second part of solvent to be added is added into the mixed reaction solution, and the tetrahydrofuran is replaced by acetonitrile or dichloroethane with the same volume according to the polarities of different reaction substrates.
3. The nonmetallic catalyzed, column-free chromatographic synthetic method of pyridyl-substituted asymmetric urea according to claim 1, characterized in that: the cyclic secondary amine of step 3) replaced by an aromatic or alicyclic amine, specifically comprising 1,2,3, 4-tetrahydroquinoline, having a primary amine (-NH) 2 ) And aliphatic amines, alicyclic amines, alcohol amines, aromatic amines, and aromatic heterocyclic amines of secondary amine (-NH-) structure.
4. The nonmetallic catalyzed, column-free chromatographic synthetic method of pyridyl-substituted asymmetric urea according to claim 1, characterized in that: the 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (IPTA) described in step 3) was replaced with a meta-and para-substituted pyridine type derivative.
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