CN113121459B - A method for preparing benzodiazepine compound using gold complex - Google Patents
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229910052737 gold Inorganic materials 0.000 title claims abstract description 62
- 239000010931 gold Substances 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims abstract description 33
- -1 benzodiazepine compound Chemical class 0.000 title claims abstract description 32
- 229940049706 benzodiazepine Drugs 0.000 title claims abstract description 27
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 64
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000003446 ligand Substances 0.000 claims abstract description 38
- GJLPUBMCTFOXHD-UPHRSURJSA-N (11z)-1$l^{2},2$l^{2},3$l^{2},4$l^{2},5$l^{2},6$l^{2},7$l^{2},8$l^{2},9$l^{2},10$l^{2}-decaboracyclododec-11-ene Chemical compound [B]1[B][B][B][B][B]\C=C/[B][B][B][B]1 GJLPUBMCTFOXHD-UPHRSURJSA-N 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 150000003003 phosphines Chemical class 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 7
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 claims description 2
- MYBSUWNEMXUTAX-UHFFFAOYSA-N 1-ethynyl-2-methylbenzene Chemical group CC1=CC=CC=C1C#C MYBSUWNEMXUTAX-UHFFFAOYSA-N 0.000 claims description 2
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 claims description 2
- GAZZTEJDUGESGQ-UHFFFAOYSA-N 1-ethynyl-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(C#C)C=C1 GAZZTEJDUGESGQ-UHFFFAOYSA-N 0.000 claims description 2
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 claims description 2
- AGAHETWGCFCMDK-UHFFFAOYSA-N 4-methoxybenzene-1,2-diamine Chemical compound COC1=CC=C(N)C(N)=C1 AGAHETWGCFCMDK-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- SSDZYLQUYMOSAK-UHFFFAOYSA-N ethynylcyclohexane Chemical group C#CC1CCCCC1 SSDZYLQUYMOSAK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 abstract description 21
- 239000003054 catalyst Substances 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000654 additive Substances 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 4
- 150000004987 o-phenylenediamines Chemical class 0.000 abstract description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000005086 pumping Methods 0.000 description 6
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 5
- 150000001557 benzodiazepines Chemical class 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BXIXXXYDDJVHDL-UHFFFAOYSA-N 4-Chloro-ortho-phenylenediamine Chemical compound NC1=CC=C(Cl)C=C1N BXIXXXYDDJVHDL-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/12—Gold compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/18—Gold
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
Abstract
The invention relates to a gold complexPreparation of benzodiazepines
A method for preparing a compound, which comprises the following steps: the benzodiazepine is prepared by taking an o-phenylenediamine compound and alkyne as raw materials and a gold complex containing a diphosphine o-carborane ligand as a catalyst through reaction at room temperature
A kind of compound is provided. Compared with the prior art, the invention adopts the gold complex containing diphosphine o-carborane ligand as the catalyst to efficiently catalyze the reaction of o-phenylenediamine compounds and alkyne to synthesize the benzodiazepine
Description
Technical Field
The invention belongs to benzodiazepines
The technical field of preparation of compounds, and relates to a method for preparing benzodiazepine by using gold complex
A method for preparing the compound.
Background
Benzodiazepines
The compounds are important heterocyclic compounds with pharmacological activity, have the functions of sedation, hypnosis, anti-inflammation, nerve resistance and the like, have potential pharmacological activity, and can be used as important synthetic intermediates of some fused ring compounds. Therefore, the study of benzodiazepines is simple and efficient
The synthetic method of the compound has important significance.
The traditional synthetic method is mainly characterized in that o-phenylenediamine and alpha, beta-unsaturation are used for synthesizingKetones, β -halo ketones, or ketone compounds are prepared by condensation reactions (Tetrahedron lett.2008,49,5302, chem.eur.j.2009,15, 8834. However, such condensation processes are less atom economical. Since alkynes are precursors for the preparation of ketone compounds, it would be desirable if benzodiazepines could be synthesized directly using alkynes as substrates
The compound can not only solve the problem of step economy, but also effectively improve the atom economy of the reaction. 2012, maiti et al reported that o-phenylenediamine and alkyne are in HgOTf 2 Catalytic synthesis of 1,5-benzodiazepine
(Tetrahedron lett.2012,53,1460). This process achieves a more atom-efficient synthesis, but uses a highly toxic mercury-containing catalyst. Liu 2012 and Luo 2014 reported the use of gold catalysts instead of mercury catalysts (j.org.chem.2012, 77,4484, j.organometat.chem.2014, 751, 438), respectively, to achieve the direct synthesis of benzodiazepines from o-phenylenediamine and alkynes
The compounds, however, require higher reaction temperatures at which the gold catalyst is easily deactivated, thereby affecting the catalytic efficiency. In 2020 Liu et al reported a gold catalyst having catalytic activity at room temperature, but the catalyst has a large usage amount, poor stability in air and high requirements for reaction conditions (Chin.J.org.chem.2020, 40,2520).
In summary, benzodiazepines were synthesized
Although the methods of the compounds are reported, the methods have defects, such as unstable catalyst, high catalyst use equivalent, additive required for reaction, long reaction time, high reaction temperature and the like, which limit the application of the methods. Thus, the synthesis of benzodiazepines under mild conditions was developed
The method for preparing the compound has very important practical significance.
Disclosure of Invention
The invention aims to provide a method for preparing benzodiazepine by using gold complex
The method of the compound has mild reaction conditions, no need of additives, high reaction rate, high yield, wide substrate range and wide industrial application prospect.
The purpose of the invention can be realized by the following technical scheme:
preparation of benzodiazepine by using gold complex
A method for preparing a compound, which comprises the following steps: the benzodiazepine is prepared by taking an o-phenylenediamine compound and alkyne as raw materials and a gold complex containing a diphosphine o-carborane ligand as a catalyst through reaction at room temperature
A compound of the class; the structural formula of the gold complex containing diphosphine o-carborane ligand is shown as follows:
wherein R is-Ph, 4-MeO-C 6 H 4 -、4-NO 2 -C 6 H 4 -or i Pr-, which is a boron hydrogen bond.
Namely, the structural formula of the gold complex containing diphosphine o-carborane ligand is shown as one of the following 1-4:
further, the preparation method of the gold complex containing diphosphine o-carborane ligand comprises the following steps:
1) Adding n-BuLi (n-butyllithium) solution to ortho-carborane (o-C) at low temperature 2 B 10 H 12 ) Stirring the solution for 20 to 40min, then heating the solution to room temperature and reacting the solution for 20 to 40min;
2) Adding halogenated phosphine, and reacting at room temperature for 1-3h;
3) Adding AuBr (aurous bromide), reacting at room temperature for 3-6h, and post-treating to obtain the gold complex containing diphosphine o-carborane ligand.
The preparation process of the gold complex containing diphosphine o-carborane ligand comprises the following steps:
further, in the step 1), the n-BuLi solution is an n-hexane solution of n-BuLi, and the orthocarborane solution is an ether solution of orthocarborane.
Further, in the step 1), the low temperature is-5 ℃ to 5 ℃.
Further, in the step 2), the halogenated phosphine is ClPR 2 Preferably ClPPh 2 、ClP(4-MeO-C 6 H 4 ) 2 、ClP(4-NO 2 -C 6 H 4 ) 2 Or ClP i Pr 2 One kind of (1).
Further, in step 3), the post-treatment process is as follows: after the reaction, the solvent was drained under reduced pressure to obtain a crude product, which was then washed (with ether as a detergent) and dried.
Furthermore, the mol ratio of the ortho-carborane to the n-BuLi to the halogenated phosphine to the AuBr is 1.0 (2.2-2.5) to 2.2-3.0 to 0.8-1.2.
Further, the method specifically comprises the following steps: dissolving gold complex containing diphosphine o-carborane ligand, o-phenylenediamine compound and alkyne in organic solvent, reacting for 3-6h at room temperature, separating and purifying to obtain benzodiazepine
A kind of compound is provided.
Furthermore, the molar ratio of the gold complex containing diphosphine o-carborane ligand, o-phenylenediamine compound and alkyne is (0.01-0.05): 1.0 (2.0-2.2).
Further, the o-phenylenediamine compound is one of o-phenylenediamine, 4-methoxy o-phenylenediamine or 4-chloro o-phenylenediamine; the alkyne is terminal alkyne, and is preferably one of phenylacetylene, 4-methylphenylacetylene, 4-methoxyphenylacetylene, 4-chlorophenylacetylene, 4-nitrophenylacetylene, 2-methylphenylacetylene or cyclohexylacetylene; the organic solvent comprises one or more of tetrahydrofuran, methanol, dichloromethane or dimethyl sulfoxide (DMSO).
Compared with the prior art, the invention has the following characteristics:
1) The invention adopts a gold complex containing diphosphine o-carborane ligand as a catalyst to efficiently catalyze the reaction of o-phenylenediamine compounds and alkyne to synthesize benzodiazepine
The compound has the advantages of low catalyst consumption (about 1.0 mol%), good selectivity, mild reaction conditions, reaction at room temperature, no need of additives, high reaction rate, high yield, wide substrate range and wide industrial application prospect.
2) The preparation method of the gold complex containing diphosphine o-carborane ligand is simple and green, the gold complex can be obtained in high yield through one-pot reaction, the yield is high, the product is simple to separate, the product is insensitive to air and water, the property is stable, and the gold complex can catalyze the reaction of o-phenylenediamine compounds and alkyne to synthesize benzodiazepine
The compound has good effect.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
Example 1:
synthesis of gold complex 1:
n-BuLi (2.2 mmol) in n-hexane was added dropwise to the o-C orthocarborane at 0 deg.C 2 B 10 H 12 (1.0 mmol) in ether solution, stirring for 30 minutes after the dropwise addition, slowly raising the temperature to room temperature, reacting for 30 minutes, and adding halogenated phosphine ClPPh 2 (2.2 mmol), continuing to react for 2 hours at room temperature, then adding AuBr (1.0 mmol) into the reaction system, continuing to react for 3 hours at room temperature, after the reaction is finished, standing and filtering, decompressing and pumping out the solvent, washing the obtained crude product with diethyl ether, and pumping out to obtain a target product 1 (yield 81%) which has the reaction formula:
1 H NMR(400MHz,CDCl 3 25 ℃) delta =7.69-7.63 (m, 8H), 7.51-7.42 (m, 12H). Theoretical value of elemental analysis C 26 B 10 H 30 P 2 AuBr: c39.56, H3.83; experimental values: c39.51, H3.90.
Example 2:
synthesis of gold complex 2:
n-BuLi (2.5 mmol) in n-hexane was added dropwise to the o-C orthocarborane at 0 deg.C 2 B 10 H 12 (1.0 mmol) in diethyl ether, stirring for 30min after dropping, slowly raising the temperature to room temperature, reacting for 30min, and adding halogenated phosphine ClP (4-MeO-C) 6 H 4 ) 2 (2.5 mmol), continuing to react at room temperature for 2 hours, then adding AuBr (1.0 mmol) into the reaction system, continuing to react at room temperature for 5 hours, after the reaction is finished, standing and filtering, decompressing and draining the solvent, washing the obtained crude product with diethyl ether, and draining to obtain a target product 2 (yield 83%), wherein the reaction formula is as follows:
1 H NMR(400MHz,CDCl 3 25 ℃ delta =7.80-7.73 (m, 8H), 7.63-7.55 (m, 8H), 3.37 (s, 12H). Theoretical value of elemental analysis C 30 B 10 H 38 O 4 P 2 AuBr: c39.62, H4.21; experimental values: c39.66 and H4.28.
Example 3:
synthesis of gold complex 3:
n-BuLi (2.3 mmol) in n-hexane was added dropwise to the o-C orthocarborane at 0 deg.C 2 B 10 H 12 (1.0 mmol) in ether solution, stirring for 30min after dropping, slowly raising the temperature to room temperature, reacting for 30min, and adding halogenated phosphine ClP (4-NO) 2 -C 6 H 4 ) 2 (3.0 mmol), continuing to react for 2 hours at room temperature, then adding AuBr (1.0 mmol) into the reaction system, continuing to react for 4 hours at room temperature, after the reaction is finished, standing and filtering, decompressing and pumping out the solvent, washing the obtained crude product with diethyl ether, and pumping out to obtain a target product 3 (yield 77%), wherein the reaction formula is as follows:
1 H NMR(400MHz,CDCl 3 25 ℃ delta =7.86-7.77 (m, 8H), 7.69-7.61 (m, 8H). Theoretical value of elemental analysis C 26 B 10 H 26 N 4 O 8 P 2 AuBr: c32.21, H2.70, N5.78; experimental values: c32.30, H2.66 and N5.82.
Example 4:
synthesis of gold complex 4:
n-BuLi (2.4 mmol) in n-hexane was added dropwise to the o-C orthocarborane at 0 deg.C 2 B 10 H 12 (1.0 mmol) of the obtained product in ether solution, continuously stirring for 30 minutes after dropwise adding, slowly raising the temperature to room temperature, continuously reacting for 30 minutes, and adding halogenated phosphine ClP i Pr 2 (2.6 mmol) and continued reaction at room temperature for 2 hours, thenThen adding AuBr (1.0 mmol) into the reaction system, continuing to react for 5 hours at room temperature, standing and filtering after the reaction is finished, decompressing and pumping out the solvent, washing the obtained crude product with diethyl ether, and pumping out to obtain a target product 4 (yield 80%), wherein the reaction formula is as follows:
1 H NMR(400MHz,CDCl 3 25 ℃ delta =2.58-2.52 (m, 4H), 1.22-1.09 (m, 24H). Theoretical value of elemental analysis C 12 B 10 H 38 P 2 AuBr: c22.90, H6.09; experimental values: c22.93 and H6.13.
Example 5:
synthesis of 1,5-benzodiazepine by catalyzing reaction of o-phenylenediamine and phenylacetylene with gold complex containing diphosphine o-carborane ligand
The compound comprises the following specific steps:
in a reaction tube, univalent gold complex and o-phenylenediamine
(1.0 mmol), phenylacetylene
Dissolving in organic solvent, reacting at room temperature for 3-6 hours, concentrating reaction liquid after the reaction is finished, and separating and purifying the crude product by column chromatography, wherein the eluent is petroleum ether: ethyl acetate =8:1, i.e. 1,5-benzodiazepine
The specific results are shown in table 1, and the reaction formula is:
TABLE 1
Example 6:
gold complex containing diphosphine o-carborane ligand is used for catalyzing o-phenylenediamine compound and alkyne to react and synthesize 1,5-benzodiazepine
The compound comprises the following specific steps:
dissolving gold complex 1 (0.01mmol, 1.0 mol%), o-phenylenediamine compound (1.0 mmol) and alkyne (2.0 mmol) in methanol (2 mL) in a reaction tube, reacting at room temperature for 3 hours, concentrating the reaction solution after the reaction is finished, separating and purifying the crude product by column chromatography, wherein the eluent is petroleum ether: ethyl acetate =8:1, to obtain the corresponding 1,5-benzodiazepine
The specific results of the compounds are shown in Table 2, and the reaction formula is as follows:
TABLE 2
Example 7:
preparation of benzodiazepine by using gold complex
A method for preparing a compound, which comprises the following steps: the benzodiazepine is prepared by taking an o-phenylenediamine compound and alkyne as raw materials and a gold complex containing a diphosphine o-carborane ligand as a catalyst through reaction at room temperature
A kind of compound is provided. The method specifically comprises the following steps: dissolving gold complex containing diphosphine o-carborane ligand, o-phenylenediamine compound and alkyne in organic solvent, reacting for 3h at room temperature, separating and purifying to obtain benzodiazepine
A kind of compound is provided. The molar ratio of the gold complex containing the diphosphine o-carborane ligand to the o-phenylenediamine compound to the alkyne is 0.05.
The preparation method of the gold complex containing diphosphine o-carborane ligand comprises the following steps:
1) Adding n-BuLi n-hexane solution into orthocarborane ether solution at 5 ℃, stirring for 20min, then heating to room temperature and reacting for 40min;
2) Adding halogenated phosphine, and reacting at room temperature for 1h;
3) Adding AuBr, reacting at room temperature for 6h, decompressing and draining the solvent after the reaction is finished to obtain a crude product, and then washing and drying the crude product to obtain the gold complex containing the diphosphine o-carborane ligand.
Wherein the molar ratio of the ortho-carborane to the n-BuLi to the halogenated phosphine to the AuBr is 1.0.
Example 8:
preparation of benzodiazepine by using gold complex
A method for preparing a compound, which comprises the following steps: the benzodiazepine is prepared by taking an o-phenylenediamine compound and alkyne as raw materials and a gold complex containing a diphosphine o-carborane ligand as a catalyst through reaction at room temperature
A kind of compound is provided. The method comprises the following steps: dissolving gold complex containing diphosphine o-carborane ligand, o-phenylenediamine compound and alkyne in organic solvent, reacting for 6h at room temperature, separating and purifying to obtain the benzodiazepine
A kind of compound is provided. The molar ratio of the gold complex containing the diphosphine o-carborane ligand to the o-phenylenediamine compound to the alkyne is 0.01.
The preparation method of the gold complex containing diphosphine o-carborane ligand comprises the following steps:
1) Adding n-BuLi n-hexane solution into orthocarborane ether solution at-5 ℃, stirring for 40min, then heating to room temperature and reacting for 20min;
2) Adding halogenated phosphine, and reacting at room temperature for 3 hours;
3) Adding AuBr, reacting at room temperature for 3h, decompressing and draining the solvent after the reaction is finished to obtain a crude product, and then washing and drying the crude product to obtain the gold complex containing the diphosphine o-carborane ligand.
Wherein the molar ratio of the ortho-carborane to the n-BuLi to the halogenated phosphine to the AuBr is 1.0.
Example 9:
preparation of benzodiazepine by using gold complex
A method for preparing a compound, which comprises the following steps: the benzodiazepine is prepared by taking an o-phenylenediamine compound and alkyne as raw materials and a gold complex containing a diphosphine o-carborane ligand as a catalyst through reaction at room temperature
A kind of compound is provided. The method comprises the following steps: dissolving gold complex containing diphosphine o-carborane ligand, o-phenylenediamine compound and alkyne in organic solvent, reacting for 5h at room temperature, separating and purifying to obtain the benzodiazepine
A kind of compound is provided. The molar ratio of the gold complex containing the diphosphine o-carborane ligand to the o-phenylenediamine compound to the alkyne is 0.03.
The preparation method of the gold complex containing diphosphine o-carborane ligand comprises the following steps:
1) Adding n-BuLi n-hexane solution into orthocarborane ether solution at 0 ℃, stirring for 30min, then heating to room temperature and reacting for 30min;
2) Adding halogenated phosphine, and reacting at room temperature for 2 hours;
3) Adding AuBr, reacting at room temperature for 5h, decompressing and draining the solvent after the reaction is finished to obtain a crude product, and then washing and drying the crude product to obtain the gold complex containing the diphosphine o-carborane ligand.
Wherein, the molar ratio of the ortho-carborane to the n-BuLi to the halogenated phosphine to the AuBr is 1.0.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (8)
1. A method for preparing a benzodiazepine compound using a gold complex, comprising:
dissolving a gold complex containing a diphosphine o-carborane ligand, an o-phenylenediamine compound and alkyne in an organic solvent, reacting at room temperature for 3-6h, and separating and purifying to obtain the benzodiazepine compound;
the structural formula of the gold complex containing diphosphine o-carborane ligand is shown as follows:
wherein R is 2 is-Ph, 4-MeO-C 6 H 4 -、4-NO 2 -C 6 H 4 -or i Pr < - > ", is a boron hydrogen bond;
the o-phenylenediamine compound is one of o-phenylenediamine, 4-methoxy-o-phenylenediamine or 4-chlorine-o-phenylenediamine; the alkyne is one of phenylacetylene, 4-methylphenylacetylene, 4-methoxyphenylacetylene, 4-chlorophenylacetylene, 4-nitrophenylacetylene, 2-methylphenylacetylene or cyclohexylacetylene; the organic solvent comprises one or more of tetrahydrofuran, methanol, dichloromethane or dimethyl sulfoxide.
2. A method of preparing benzodiazepine compound using gold complex according to claim 1, wherein said method of preparing gold complex comprising a bisphosphine orthocarborane ligand comprises the steps of:
1) Will be at low temperaturen-Adding the BuLi solution into the ortho carborane solution, stirring for 20-40min, then heating to room temperature and reacting for 20-40min;
2) Adding halogenated phosphine, and reacting at room temperature for 1-3h;
3) Adding AuBr, reacting at room temperature for 3-6h, and post-treating to obtain the gold complex containing diphosphine o-carborane ligand.
3. A method for preparing a benzodiazepine compound using a gold complex as claimed in claim 2, wherein, in step 1), the compound is selected from the group consisting ofAs described inn-The BuLi solution isn-The solution of BuLi in n-hexane is an ether solution of o-carborane.
4. A method for preparing a benzodiazepine compound using a gold complex as claimed in claim 2, wherein, in step 1), said low temperature is-5 ℃ to 5 ℃.
5. The method for preparing benzodiazepine compound using gold complex as claimed in claim 2, wherein in step 2), said halogenated phosphine is ClPPh 2 、ClP(4-MeO-C 6 H 4 ) 2 、ClP(4-NO 2 -C 6 H 4 ) 2 Or ClP i Pr 2 One kind of (1).
6. A method for preparing a benzodiazepine compound using a gold complex as claimed in claim 2, wherein, in step 3), the post-treatment process is: and after the reaction is finished, decompressing and draining the solvent to obtain a crude product, and then washing and drying the crude product.
7. A method for preparing benzodiazepine compound using gold complex as claimed in claim 2, wherein said orthocarborane, said ligand or ligand is selected from the group consisting of a ligand, a ligand and a pharmaceutically acceptable salt thereof,nThe mol ratio of BuLi to the halogenated phosphine to AuBr is 1.0 (2.2-2.5) to (2.2-3.0) to (0.8-1.2).
8. The method for preparing a benzodiazepine compound using a gold complex according to claim 1, wherein the molar ratio of the gold complex containing a bisphosphine ortho-carborane ligand, the orthophenylenediamine compound and the alkyne is (0.01-0.05): 1.0 (2.0-2.2).
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