CN114276375A - Synthesis method of 1,3, 2-benzodiazepine borane ketone and derivatives thereof - Google Patents
Synthesis method of 1,3, 2-benzodiazepine borane ketone and derivatives thereof Download PDFInfo
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- 229940049706 benzodiazepine Drugs 0.000 title claims abstract description 28
- SEDJKFXXCVUAQN-UHFFFAOYSA-N oxomethylideneboron Chemical compound [B]=C=O SEDJKFXXCVUAQN-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 19
- MLSXBTKTDZUPHO-UHFFFAOYSA-N B1=[C-]C(C=C1)=O Chemical compound B1=[C-]C(C=C1)=O MLSXBTKTDZUPHO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000009833 condensation Methods 0.000 claims abstract description 6
- 230000005494 condensation Effects 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 5
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 229940125782 compound 2 Drugs 0.000 claims description 15
- 229940125904 compound 1 Drugs 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- -1 p-phenylphenyl Chemical group 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000005504 styryl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 abstract description 37
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 abstract description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
- 239000007787 solid Substances 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- QWMJEUJXWVZSAG-UHFFFAOYSA-N (4-ethenylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=C)C=C1 QWMJEUJXWVZSAG-UHFFFAOYSA-N 0.000 description 1
- XPEIJWZLPWNNOK-UHFFFAOYSA-N (4-phenylphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1C1=CC=CC=C1 XPEIJWZLPWNNOK-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- HDIWKNXVBQPJCO-UHFFFAOYSA-N ethyl 2-methylsulfanyl-6-oxo-1h-pyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)NC1=O HDIWKNXVBQPJCO-UHFFFAOYSA-N 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N flavanone Chemical compound O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a synthesis method of 1,3, 2-benzodiazepine borane ketone and derivatives thereof, which is characterized in that phenylboronic acid and derivatives thereof, anthranilamide and derivatives thereof are subjected to dehydration condensation in a solvent to obtain the 1,3, 2-benzodiazepine borane ketone and derivatives thereof. According to the method, phenylboronic acid and the derivatives thereof, anthranilamide and the derivatives thereof are subjected to dehydration condensation in a solvent to obtain the 1,3, 2-benzodiazepine borolidone and the derivatives thereof.
Description
Technical Field
The invention relates to 1,3, 2-benzodiazepine borolidone [ R-B (aam) ] and derivatives thereof, in particular to a synthesis method of 1,3, 2-benzodiazepine borolidone and derivatives thereof.
Background
Organoboron compounds play an important role in pharmaceutical synthesis, medicinal chemistry and biochemistry. Organoboron compounds are particularly popular organometallic reagents in modern synthetic organic chemistry and are useful for building carbon-carbon and carbon-heteroatom bonds due to their wide availability and multi-functional compatibility. In addition, aromatic compounds containing a boron (B) -nitrogen (N) bond are also popular in the fields of material chemistry and fluorescence imaging. The construction of 1,3, 2-benzodiazepineborane ketones reported in the literature mainly comprises the following methods: (1) phenylboronic acids are condensed with anthranilamides in toluene reflux (1 Ihara, H.; Koyanagi, M.; Suginome, M.organic Letters2011,13, 2662-; (2) catalytic Synthesis of phenylboronic acid and anthranilamide in metals such as Ni/Pd (document 2Wang, H. -J.; Zhang, M.; Li, W. -J.; Ni, Y.; Lin, J.; Zhang, Z. -H. advanced Synthesis & Catalysis 2019,361, 5018-; (3) pd-catalyzed reaction of potassium phenyltrifluoroborate with anthranilamide (ref 3Davies, G.H.M.; Mukhtar, A.; Saeednia, B.; Sherafat, F.; Kelly, C.B.; Molander, G.A. J.Org.chem.2017,82, 5380-containing 5390); (4) aryl halides are reacted with (pin) B-B (aam) (pin ═ pinacol ester) to synthesize 1,3, 2-benzodiazepine borolidones (document 4Kamio, s.; Kageyuki, i.; Osaka, i.; Hatano, s.; Abe, m.; Yoshida, h.chem.comm.2018, 54, 9290-. Although these methods have high yield, expensive metal catalysts (such as nickel and palladium) are used in these reactions, the reaction temperature is high, the reaction time is long, and various complex reagents are required. Therefore, from the viewpoint of green chemistry, it is necessary to develop a simple, efficient and clean method for synthesizing 1,3, 2-benzodiazepine borolidone.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for synthesizing 1,3, 2-benzodiazepine borolidone and derivatives thereof.
Except for special description, the parts are parts by weight, and the percentages are mass percentages.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing 1,3, 2-benzodiazepine borane ketone and derivatives thereof is characterized by comprising the following steps: dehydrating and condensing the compound 1 and the compound 2 to obtain the 1,3, 2-benzodiazepine borane ketone and the derivative thereof.
The reaction route is as follows:
wherein,
R1are each independentlyHydrogen, methoxy, halogen;
R2is independently hydrogen, C1-6Alkyl, thiophene, halogen, p-phenylphenyl, nitro, hydroxyl and styryl.
In the above methods, in the compound 1 and the compound 2, R1And R2Can be independently ortho-position, meta-position or para-position, can be simultaneously substituted by the ortho-position, the meta-position and the para-position, and can also be independently substituted.
In the above method, the solvent used for dehydration condensation is selected from one or more of water, methanol, ethanol, tetrahydrofuran, N-dimethylformamide, ethyl acetate, dimethyl sulfoxide and toluene; ethyl acetate is preferred. Further, the weight ratio of the solvent to the anthranilamide is 1-40 times.
In the above method, the molar ratio of the compound 1 to the compound 2 is 1 (1.0 to 1.6), preferably 1 (1.0 to 1.2).
The invention discloses a synthesis method of 1,3, 2-benzodiazepine borane ketone and derivatives thereof, which is characterized by comprising the following steps: adding the compound 1, the compound 2 and a solvent into a reactor (such as a reaction bottle, a reaction kettle and the like), stirring at room temperature, reacting for 1-4 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain the 1,3, 2-benzodiazepine borane ketone and the derivative thereof.
A method for synthesizing 1,3, 2-benzodiazepine borane ketone and derivatives thereof is characterized by comprising the following steps: adding the compound 1, the compound 2 and a solvent into a reactor (such as a reaction bottle, a reaction kettle and the like), stirring at room temperature, reacting for 1-4 hours, terminating the reaction, filtering, concentrating, purifying and drying to obtain the 1,3, 2-benzodiazepine borolidone and derivatives thereof; the solvent is ethyl acetate, and the weight ratio of the solvent to the anthranilamide is 1-40 times; the molar ratio of the compound 1 to the compound 2 is 1 (1.0-1.2).
Has the advantages that:
the invention provides a synthesis method of 1,3, 2-benzodiazepine borane ketone and derivatives thereof, which comprises the step of stirring, dehydrating and condensing a compound 1 and a compound 2 in a solvent to obtain the 1,3, 2-benzodiazepine borane ketone and the derivatives thereof in one step. Compared with the prior art, the method provided by the invention has the advantages that the compound 1 and the compound 2 are subjected to dehydration condensation in the solvent to obtain the 1,3, 2-benzodiazepine borone and the derivative thereof, and the method can realize higher yield without using a catalyst or other additives. The method has the advantages of mild reaction, high yield, low cost, little pollution, simple reaction operation and greenness.
Detailed Description
Definition of
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "C" as used herein1-6Alkyl "means a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and the like.
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. The raw materials and reagents used in the invention are all commercial products.
Example 1
Phenylboronic acid (1.0g, 8.30mmol), anthranilamide (1.4g, 10.00mmol) and ethyl acetate (20ml) were added to a dry clean reaction flask, and after stirring for 3 hours, the reaction was monitored by TLC plate for completion, the reaction was filtered, the filtrate was collected, concentrated under reduced pressure, and purified to give 1.60g of a white solid with a yield of 88%.
Referring to the above examples, the inventors conducted a search for reaction conditions for synthesizing 1,3, 2-benzodiazepine borolidone by dehydrating condensation of phenylboronic acid and anthranilamide, and the results are shown in Table 1. Anthranilamide with phenylboronic acid and titanium tetrachloride (TiCl)4) The reaction was carried out as a dehydrating agent at room temperature in Tetrahydrofuran (THF) for 4 hours, and the yield of the product was 93% (Table 1, entry 1). The structure of the product was determined by NMR analysis. Free of TiCl at room temperature4In the case ofThe reaction still achieved a 90% yield (table 1, entry 2). To select the most suitable solvent, the reaction was carried out in different solvents (including ethanol, methanol, N-dimethylformamide, toluene, ethyl acetate, etc.) for 1 hour (table 1, entries 3-10), and the highest yield (70%) was found to be obtained in ethyl acetate (table 1, entry 8). The yield increased gradually with longer reaction time, and the yield of Ar-B (aam) was as high as 93% (Table 1, entry 13). However, the yields did not increase further with increasing reaction time and temperature (Table 1, entries 14-16). Therefore, the optimal conditions of the reaction system are that the reaction is carried out in ethyl acetate at room temperature for 3 hours, and the reaction yield is highest and reaches 93 percent. The reaction route is as follows:
TABLE 1 screening of reaction conditionsa。
aThe reaction was carried out using phenylboronic acid (1mmol) and anthranilamide (1.2 eq).
bIsolated in yield.
With reference to the above examples, the inventors began to investigate the general applicability of this reaction. The results are summarized in Table 2 and show that phenylboronic acid contains different substituents in the para position, such as methyl, ethyl, isopropyl and halogen groups, giving yields of 80% to 95% of the product (tables 2, 3b-3d, 3g, 3j, 3 k). In addition, one or two different groups are introduced to the meta position of the phenylboronic acid, and the yield of the product (shown in tables 2, 3e, 3h and 3l) can reach 80-96%. Likewise, the reaction is also applicable to boronic acids containing different aryl groups, such as 4-vinylphenylboronic acid, 2-thiopheneboronic acid and 4-biphenylboronic acid, in reaction yields ranging from 82% to 85% (table 2, 3p-3r), whereas the introduction of a halogen ortho to the phenylboronic acid gives products (table 2, 3i) in yields of only 58%, in particular when two substituents or methyl groups are introduced ortho to the phenylboronic acid, which do not react with anthranilamide (table 2, 3f), indicating that steric hindrance has a great influence on the reaction. The reaction effect is good when the phenylboronic acid has strong electron-withdrawing substituents such as nitro, and the yield of the obtained target product 3o reaches 94%. However, when phenylboronic acid carries a hydroxyl group, no product formation is observed (table 23 n). Therefore, the electronic effect of the phenylboronic acid substituent has a significant effect on the reaction result. To further verify the substrate range of the reaction, anthranilamides each having a substituent on the benzene ring were used. All products (Table 2, 3s-3X) were obtained in good yields.
TABLE 2 substrate extension
aThe reaction was carried out using a phenylboronic acid derivative (1mmol) and anthranilamide (1.2 equivalents).
bThe reaction was carried out with phenylboronic acid (1mmol) and substituted anthranilamide (1.2 equiv.).
cThe reaction was carried out using substituted phenylboronic acid (1mmol) and substituted anthranilamide (1.2 equiv.).
dNo reaction occurred.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
EXAMPLE 1 general procedure for the Synthesis of 1,3, 2-benzodiazepine Boronone derivatives (3a-3r)
Adding phenylboronic acid (0.12g, 1mmol), anthranilamide (0.16g, 1.2mmol) and ethyl acetate (2 ml) into a dry and clean reaction bottle, stirring for 3 hours, monitoring the reaction completion by a thin-layer chromatography dot plate, filtering the reaction solution, collecting filtrate, concentrating under reduced pressure, and purifying to obtain the required product.
General procedure for the Synthesis of 1,3, 2-Benzodiazaborolidone derivatives (3s-3X)
Adding phenylboronic acid (0.12g, 1mmol), anthranilamide (0.16g, 1.2mmol) and ethyl acetate (2 ml) into a dry and clean reaction bottle, stirring for 3 hours, monitoring the reaction completion by a thin-layer chromatography dot plate, filtering the reaction solution, collecting filtrate, concentrating under reduced pressure, and purifying to obtain the required product.
Nuclear magnetic data of target product
2-phenyl-2, 3-dihydrobenzo [1,3,2 ]]Benzodiazepineborolidone (3a), white solid, m.p.209.8-212 ℃;1H NMR (600MHz,DMSO-d6)δ9.70(s,1H),9.33(s,1H),8.05(dd,J＝14.6,7.6Hz,3H),7.58(t,J ＝7.6Hz,1H),7.48(dt,J＝25.7,7.6Hz,4H),7.12(t,J＝7.5Hz,1H).13CNMR(151MHz, DMSO-d6) Delta 166.78,145.95,133.85,133.78,130.98,128.41,128.28,121.29,119.25,118.62.2- (p-tolyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3b), white solid, m.p.265-266 deg.C1H NMR(600MHz,DMSO-d6)δ9.64(s,1H),9.30(s,1H),8.03(d,J＝8.0Hz,1H),7.90(s, 1H),7.85(d,J＝7.3Hz,1H),7.60–7.55(m,1H),7.45(d,J＝8.1Hz,1H),7.34(t,J＝7.4 Hz,1H),7.30(d,J＝7.5Hz,1H),7.11(t,J＝7.5Hz,1H),2.38(s,3H).13C NMR(151MHz, DMSO-d6)δ166.76,145.98,137.14,134.39,133.83,131.58,130.87,128.40,128.21,121.23, 119.24,118.60,21.58.
2- (4-ethylphenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3c), white solid, m.p.242.8-243.5 deg.C1H NMR(600MHz,DMSO-d6)δ9.63(s,1H),9.26(s,1H),8.02(d,J＝8.0Hz,1H),7.98(d, J＝7.7Hz,2H),7.56(t,J＝7.6Hz,1H),7.43(d,J＝8.1Hz,1H),7.29(d,J＝7.6Hz,2H), 7.12–7.07(m,1H),2.65(q,J＝7.6Hz,2H),1.21(t,J＝7.5Hz,3H).13C NMR(151MHz, DMSO-d6)δ166.78,146.87,146.01,133.91,133.81,128.39,127.78,121.16,119.19,118.56, 28.74,15.93.
2- (4-isopropylphenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepine borolidone (3d) as a grey solid m.p.224.0-226.5 deg.C1H NMR(600MHz,DMSO-d6)δ9.63(s,1H),9.25(s,1H),8.01(d,J＝ 6.4Hz,1H),7.97(d,J＝7.8Hz,2H),7.56(t,J＝7.6Hz,1H),7.42(d,J＝8.1Hz,1H),7.32 (d,J＝7.8Hz,2H),7.09(t,J＝7.5Hz,1H),2.92(p,J＝6.9Hz,1H),1.23(d,J＝6.9Hz,6H). 13C NMR(151MHz,DMSO-d6)δ166.78,151.45,146.01,133.93,133.81,128.39,126.31, 121.17,119.19,118.56,33.99,24.21.
2- (m-tolyl) -2, 3-dihydrobenzo [1,3, 2%]Benzodiazepineborolidone (3e) as a white solid, m.p.219.1-221.6 deg.C1H NMR(600MHz,DMSO-d6)δ9.63(s,1H),9.28(s,1H),8.02(d,J＝7.9Hz,1H),7.89(s, 1H),7.84(d,J＝7.3Hz,1H),7.59–7.54(m,1H),7.44(d,J＝8.1Hz,1H),7.33(t,J＝7.4 Hz,1H),7.29(d,J＝7.5Hz,1H),7.10(t,J＝7.5Hz,1H),2.36(s,3H).13C NMR(151MHz, DMSO-d6)δ166.76,145.98,137.14,134.39,133.83,131.58,130.87,128.40,128.21,121.23, 119.24,118.60,21.58.
2- (4-chlorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3g) white solid m.p.256-257 deg.C1H NMR(600MHz,DMSO-d6)δ9.77(s,1H),9.39(s,1H),8.08(d,J＝8.4Hz,2H),8.03(d,J ＝7.9Hz,1H),7.58(t,J＝6.8Hz,1H),7.54(s,2H),7.43(d,J＝8.3Hz,1H),7.14–7.09(m, 1H).13C NMR(151MHz,DMSO-d6)δ165.65,144.75,135.05,134.62,132.84,127.35, 127.29,120.37,118.21,117.56.
2- (3-chlorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3h) as a white solid, m.p.245.6-248.9 deg.C1H NMR(600MHz,DMSO-d6)δ9.82(s,1H),9.44(s,1H),8.17–8.13(m,1H),8.07–8.01(m, 2H),7.60(t,J＝6.8Hz,1H),7.55(d,J＝9.1Hz,1H),7.49(t,J＝7.7Hz,1H),7.44(d,J＝ 8.2Hz,1H),7.14(t,J＝7.5Hz,1H).13C NMR(151MHz,DMSO-d6)δ166.70,145.76, 133.94,133.75,133.36,132.29,130.76,130.30,128.42,121.52,119.35,118.65.
2- (2-chlorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3i) as a white solid, m.p.181.6-183.1 deg.C1H NMR(600MHz,DMSO-d6)δ9.50(s,1H),9.32(s,1H),8.02(d,J＝8.0Hz,1H),7.56(t,J＝ 7.7Hz,2H),7.49–7.44(m,2H),7.38(t,J＝7.0Hz,1H),7.31(d,J＝8.1Hz,1H),7.13(t,J ＝7.0Hz,1H).13C NMR(151MHz,DMSO-d6)δ166.21,145.63,137.14,135.22,133.84, 131.47,129.05,128.40,126.81,121.57,119.36,118.61.
2- (4-bromophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3j) as a white solid, m.p.257-258 deg.C1H NMR(600MHz,DMSO-d6)δ9.76(s,1H),9.38(s,1H),8.01(dd,J＝12.1,8.9Hz,3H), 7.66(d,J＝8.3Hz,2H),7.60–7.56(m,1H),7.42(d,J＝8.3Hz,1H),7.12(t,J＝7.5Hz, 1H).13C NMR(151MHz,DMSO-d6)δ166.70,145.80,135.89,133.92,131.27,128.41, 125.14,121.45,119.28,118.62.
2- (4-fluorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3k) as a white solid, m.p.257.6-262.3 deg.C1H NMR(600MHz,DMSO-d6)δ9.73(s,1H),9.33(s,1H),8.15–8.09(m,2H),8.02(d,J＝7.9 Hz,1H),7.60–7.55(m,1H),7.42(d,J＝8.3Hz,1H),7.29(t,J＝9.0Hz,2H),7.11(t,J＝ 8.1Hz,1H).13C NMR(151MHz,DMSO-d6)δ165.67,164.22,162.58,144.82,135.28, 135.23,132.81,127.33,120.26,118.11,117.50,114.30,114.17.
2- (3, 5-dichlorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3l) as a white solid, m.p.286-287 deg.C1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),9.49(s,1H),8.11(d,J＝1.9Hz,2H),8.02(d,J ＝6.4Hz,1H),7.71(s,1H),7.62–7.57(m,1H),7.40(d,J＝8.2Hz,1H),7.16–7.12(m, 1H).13C NMR(151MHz,DMSO-d6)δ166.57,145.57,134.65,134.03,132.16,130.24, 128.42,121.74,119.44,118.67.
2- (4-Nitrophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepine borolidone (3o) as yellow solid with m.p > 300 deg.C1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),9.60(s,1H),8.30(q,J＝8.7Hz,4H),8.05(d,J ＝7.9Hz,1H),7.61(t,J＝6.8Hz,1H),7.45(d,J＝8.1Hz,1H),7.18–7.13(m,1H).13C NMR(151MHz,DMSO-d6)δ166.63,149.31,145.62,135.12,134.01,128.43,122.79, 121.79,119.49,118.78.
2- (thien-2-yl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3p) as a white solid, m.p.201-202.3 deg.C1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),9.43(s,1H),8.04(t,J＝8.2Hz,3H),7.51(d,J＝ 7.1Hz,2H),7.48(d,J＝7.2Hz,2H),7.15(d,J＝8.5Hz,1H).13C NMR(151MHz, DMSO-d6) (E) -2-styrene-2, 3-dihydrobenzo [1,3,2 ] benzenediol [ delta 166.09,147.04,138.36,133.78,131.19,130.51,128.34,121.46,118.17,117.90 ]]Benzodiazepineborolidone (3q) as a white solid, m.p.199.8-203.1 deg.C1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),9.33(s,1H),8.05(dd,J＝15.5,7.1Hz,3H), 7.57(dd,J＝16.4,7.4Hz,3H),7.45(d,J＝8.1Hz,1H),7.14–7.09(m,1H),6.79(dd,J＝ 17.6,10.9Hz,1H),5.97(d,J＝17.6Hz,1H),5.35(d,J＝11.0Hz,1H).13C NMR(151MHz, DMSO-d6)δ165.70,144.89,138.45,135.97,133.07,132.79,127.35,124.95,120.22,118.19, 117.54,114.75.
2- ([1,1' -Biphenyl)]-4-yl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3r) as a white solid, m.p.287-287.5 deg.C1H NMR(600MHz,DMSO-d6)δ9.76(s,1H),9.39(s,1H),8.17(d,J＝7.9Hz,2H),8.04(d, J＝6.3Hz,1H),7.76(dd,J＝7.6,4.4Hz,4H),7.59(t,J＝8.4Hz,1H),7.52–7.45(m,3H), 7.40(t,J＝7.4Hz,1H),7.12(t,J＝7.8Hz,1H).13CNMR(151MHz,DMSO-d6)δ166.79, 145.98,142.50,140.29,134.49,133.87,129.45,128.43,128.25,127.25,126.49,121.31, 119.29,118.63.
7-chloro-2-phenyl-2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3s) as a white solid, m.p.289.4-290.3 deg.C1H NMR(600MHz,DMSO-d6)δ9.75(s,1H),9.29(s,1H),8.02(dd,J＝10.2,5.6Hz,2H), 7.94(d,J＝4.6Hz,1H),7.56(d,J＝7.1Hz,1H),7.43(d,J＝8.1Hz,1H),7.31(t,J＝4.0Hz, 1H),7.10(t,J＝7.5Hz,1H).13C NMR(151MHz,DMSO-d6)δ166.49,145.87,136.81, 133.87,132.94,129.09,128.41,121.30,119.26,118.60.
7-chloro-2- (4-chlorophenyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepine borolidone (3t) white solid m.p. > 300 deg.C1H NMR(600MHz,DMSO-d6)δ9.88(s,1H),9.47(s,1H),8.03(dd,J＝22.1,8.2Hz,3H), 7.54(d,J＝7.9Hz,2H),7.48(s,1H),7.15(d,J＝8.5Hz,1H).13C NMR(151MHz, DMSO-d6)δ166.00,146.92,138.39,136.33,135.68,130.52,128.43,121.60,118.19,117.89.7-chloro-2- (p-tolyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3u) white solid m.p. > 300 deg.C1H NMR(600MHz,DMSO-d6)δ9.76(s,1H),9.35(s,1H),7.96(dd,J＝39.2,8.0Hz,3H), 7.48(s,1H),7.27(d,J＝7.6Hz,2H),7.13(d,J＝8.7Hz,1H),2.36(s,3H).13C NMR(151 MHz,DMSO-d6)δ166.06,147.10,140.93,138.31,133.86,130.52,129.05,121.36,118.10, 117.82,21.67.
6-methoxy-2-phenyl-2, 3-dihydrobenzo [1,3,2 ]]Benzodiazepineborolidone (3v) as a white solid m.p.224.7-225.5 deg.C1H NMR(600MHz,DMSO-d6)δ9.77(s,1H),9.28(s,1H),8.08(d,J＝ 7.4Hz,2H),7.55(s,1H),7.51–7.43(m,4H),7.26(dd,J＝8.8,2.9Hz,1H),3.83(s,3H). 13C NMR(151MHz,DMSO-d6)δ166.73,154.09,140.17,133.66,130.80,128.26,122.77, 120.08,119.57,109.45,55.77.
6-methoxy-2- (p-tolyl) -2, 3-dihydrobenzo [1,3,2]Benzodiazepine borolidone (3w) white solid m.p.262.2-264.5 deg.C1H NMR(600MHz,DMSO-d6)δ9.67(s,1H),9.19(s,1H),7.96(d,J＝ 7.9Hz,2H),7.51(d,J＝3.0Hz,1H),7.41(d,J＝8.8Hz,1H),7.29–7.20(m,3H),3.81(s, 3H),2.36(s,3H).13C NMR(151MHz,DMSO-d6)δ166.70,153.99,140.39,140.22,133.71, 128.96,122.73,120.00,119.48,109.44,55.77,21.64.
2- (4-chlorophenyl) -6-methoxy-2, 3-dihydrobenzo [1,3,2]Benzodiazepineborolidone (3X) white solid m.p.298.3-299.2 deg.C1H NMR(600MHz,DMSO-d6)δ9.79(s,1H),9.35(s,1H),8.06(d,J＝ 8.0Hz,2H),7.62–7.43(m,3H),7.39(d,J＝8.9Hz,1H),7.24(dd,J＝8.8,3.1Hz,1H), 3.81(s,3H).13C NMR(151MHz,DMSO-d6)δ166.61,154.16,140.00,135.92,135.55, 128.33,122.81,120.07,119.60,109.43,55.79。
Claims (10)
1. A method for synthesizing 1,3, 2-benzodiazepine borolidone [ R-b (aam) ], and derivatives thereof, characterized in that: the compound 1 and the compound 2 are dehydrated and condensed; the reaction route is as follows:
wherein,
R1is hydrogen, methoxy, halogen independently; r2Is independently hydrogen, C1-6Alkyl, thiophene, halogen, p-phenylphenyl, nitro, hydroxyl and styryl.
2. The method of claim 1, wherein: the halogen is selected from fluorine, chlorine, bromine or iodine.
3. The method of claim 1, wherein: said C is1-6The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and the like.
4. The method of claim 1, wherein: in the compounds 1 and 2, R1Or R2Is independently ortho, meta or para; is simultaneously substituted or singly substituted at ortho, meta and para positions.
5. The method of claim 1, wherein: the solvent used in dehydration condensation is one or a combination of several of water, methanol, ethanol, tetrahydrofuran, N-dimethylformamide, ethyl acetate, dimethyl sulfoxide and toluene.
6. The method of claim 5, wherein: the solvent is selected from ethyl acetate.
7. The method of claim 5 or 6, wherein: the weight ratio of the solvent to the compound 2 is 1 to 40 times.
8. The method of claim 5 or 6, wherein: the molar ratio of the compound 1 to the compound 2 is 1 (1.0-1.6), preferably 1 (1.0-1.2).
9. The method according to any one of claims 1 to 6, characterized by the following steps: adding the compound 1, the compound 2 and a solvent into a reactor, reacting for 1-4 hours at room temperature, terminating the reaction, filtering, concentrating, purifying and drying to obtain the 1,3, 2-benzodiazepine borane ketone and the derivative thereof.
10. The method of claim 1, wherein the steps of: adding the compound 1, the compound 2 and a solvent into a reactor, reacting for 1-4 hours at room temperature, terminating the reaction, filtering, concentrating, purifying and drying to obtain 1,3, 2-benzodiazepine borone and derivatives thereof; the solvent is ethyl acetate; the weight ratio of the solvent to the compound 2 is 1-40 times; the molar ratio of the compound 1 to the compound 2 is 1 (1.0-1.2).
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| CN115385946A (en) * | 2022-07-06 | 2022-11-25 | 重庆医科大学 | Iminoborate, and synthesis method and application thereof |
| CN115611935A (en) * | 2022-07-06 | 2023-01-17 | 重庆医科大学 | Dioxazaboroline, its synthesis and use |
| CN115611935B (en) * | 2022-07-06 | 2024-03-26 | 重庆医科大学 | Dioxazaborolin and synthetic method and application thereof |
| CN115197261B (en) * | 2022-07-06 | 2024-05-03 | 重庆医科大学 | Synthesis method of oxadiazine boron derivative |
| CN115385946B (en) * | 2022-07-06 | 2024-05-07 | 重庆医科大学 | Iminoborates and methods of synthesis and use thereof |
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