CN110256365B - Method for preparing benzodiazepine derivative by catalysis of dichlorotitanocene - Google Patents
Method for preparing benzodiazepine derivative by catalysis of dichlorotitanocene Download PDFInfo
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- CN110256365B CN110256365B CN201910548655.5A CN201910548655A CN110256365B CN 110256365 B CN110256365 B CN 110256365B CN 201910548655 A CN201910548655 A CN 201910548655A CN 110256365 B CN110256365 B CN 110256365B
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- 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
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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- 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
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- 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
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
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- 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
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
Abstract
The invention discloses a method for preparing benzodiazepine compounds by catalyzing dichlorotitanocene, which takes 3-butyne-2-ketone compounds and o-phenylenediamine compounds as raw materials, ethanol or methanol as a solvent and an accelerant, dichlorotitanocene as a catalyst and isophthalic acid, 2-hydroxynicotinic acid or salicylic acid as a ligand, and can prepare 2, 4-diphenyl-3-H-1, 5-benzodiazepine derivatives with high efficiency and high yield. The catalyst used in the invention has the advantages of low dosage, low price, no toxicity, stability to air, mild reaction conditions, short time and simple operation, and the 2, 4-diphenyl-3-H-1, 5-benzodiazepine derivative can be obtained by separating the product through simple column chromatography after the reaction is finished, so that a new low-cost, green and efficient way is developed for the preparation of the 2, 4-diphenyl-3-H-1, 5-benzodiazepine derivative, and the preparation method has a wide application prospect.
Description
Technical Field
The invention belongs to the technical field of synthesis of benzodiazepine compounds, and particularly relates to a method for efficiently preparing the benzodiazepine compound by using isophthalic acid, 2-hydroxynicotinic acid or salicylic acid as a ligand to promote dichlorotitanocene to catalyze the reaction of a 3-butyn-2-one compound and an o-phenylenediamine compound.
Background
Benzodiazepines are a ubiquitous class of alkaloid compounds that are used in a variety of fields due to their biological and high pharmacological activities, including alcohol withdrawal symptoms, insomnia, anxiety, anti-inflammatory, anti-spasmodic, sedative and analgesic agents, some of which may be used to treat cancer, cardiovascular disease and aids.
The existing methods for synthesizing benzodiazepine compounds are roughly three, namely, reacting 1, 3-diketone compounds with o-phenylenediamine, reacting nitrile groups or other unsaturated functional groups with o-phenylenediamine, and reacting ketene or acetylene with o-phenylenediamine. Most of the existing methods use relatively harsh reaction conditions such as strong acid, strong alkali or microwave assisted methods, and the used metal catalyst also has the defects of large dosage, high price and the like, so that the development of a catalytic method which has the advantages of low catalyst price, small dosage, environmental friendliness, stability, high efficiency and mild conditions has important significance for the preparation of the benzodiazepine compounds.
Disclosure of Invention
The invention aims to overcome the defects of the existing preparation method of the benzodiazepine compound and provide a method for efficiently preparing the benzodiazepine derivative compound, which has the advantages of simple operation, mild reaction conditions, wide substrate applicability and high efficiency.
The technical scheme for solving the technical problems is as follows: adding a 3-butyne-2-ketone compound shown in a formula I and an o-phenylenediamine compound shown in a formula II into an organic solvent, adding titanocene dichloride and a ligand, reacting at room temperature for 6-24 hours, and separating and purifying a product to obtain a benzodiazepine compound shown in a formula III;
in the formula R1And R2Each independently an aryl or substituted aryl, such as: epi-phenyl, C1～C4Alkyl-substituted phenyl, C1～C4Alkoxy-substituted phenyl, halophenyl, trifluoromethyl-substituted phenyl, nitro-substituted phenyl, etc.; r3、R4、R5、R6Each independent representative H, C1～C4Alkyl radical, C1～C4Any one of alkoxy, F, Cl and Br.
The organic solvent is any one of ethanol and methanol, preferably ethanol.
The ligand is any one of isophthalic acid, 2-hydroxynicotinic acid and salicylic acid, preferably isophthalic acid.
In the preparation method, the mol ratio of the 3-butyne-2-ketone compound to the o-phenylenediamine compound is preferably 1: 1.1-1.5.
In the preparation method, the addition amount of the titanocene dichloride is preferably 1 to 3 percent of the molar amount of the 3-butyne-2-ketone compound.
In the above preparation method, the addition amount of the ligand is preferably 2 to 6 percent of the molar amount of the 3-butyne-2-ketone compound.
The method takes ethanol or methanol as a solvent, dichlorotitanocene as a catalyst and isophthalic acid, 2-hydroxynicotinic acid or salicylic acid as a ligand, and can efficiently catalyze the direct reaction of 3-butyne-2-ketone compounds and o-phenylenediamine compounds to obtain benzodiazepine compounds. The method has the advantages of low catalyst consumption, low price, no toxicity, stability to air, mild reaction conditions, short time, no toxicity of a solvent, simple operation and high atom economy, and after the reaction is finished, the benzodiazepine compound with wide biological activity and medicinal value can be obtained by separating the product through simple column chromatography, so that a new low-cost, green and efficient way for preparing the benzodiazepine compound is developed, and the method has wide application prospect.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
Preparing 2, 4-diphenyl-3-H-1, 5-benzodiazepine with the structural formula
Adding 0.0025g (0.01mmol) of titanocene dichloride, 0.0033g (0.02mmol) of isophthalic acid, 0.065g (0.6mmol) of o-phenylenediamine, 0.103g (0.5mmol) of 1, 4-diphenyl-3-butyn-2-one and 1mL of ethanol into a reaction bottle, stirring and reacting for 5 hours at room temperature, stopping the reaction, removing the ethanol by rotary evaporation, and separating by using a silica gel column (a washing and dehydrating machine is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10: 1) to obtain the 2, 4-diphenyl-3-H-1, 5-benzodiazepine with the yield of 96 percent, wherein the spectral data of the product are as follows:1H NMR(600MHz,CDCl3)δ7.95-7.81(m,4H),7.53(dd,J＝6.1,3.5Hz,2H),7.387.31(m,6H),7.27(dd,J＝6.1,3.5Hz,2H),7.18(s,0H),1.53(s,1H)；13C NMR(101MHz,CDCl3)δ154.26,140.83,137.34,130.69,128.83,128.77,128.22,125.54,35.01.
comparative example 1
In example 1, ethanol was replaced with an equal volume of toluene, and other steps were the same as in example 1, thus failing to obtain 2, 4-diphenyl-3-H-1, 5-benzodiazepine.
Comparative example 2
In example 1, ethanol used was replaced with an equal volume of DMF and the other steps were the same as in example 1 to obtain 2, 4-diphenyl-3-H-1, 5-benzodiazepine in 28% yield.
Example 2
Preparing 2- (4-fluorophenyl) -4-phenyl-3-H-1, 5-benzodiazepine with the structural formula
In this example, the equimolar 1- (4-fluorophenyl) -4-phenyl-3-butyn-2-one was used instead of the 1, 4-diphenyl-3-butyn-2-one used in example 1, and the other procedures were the same as in example 1 to give 2- (4-fluorophenyl) -4-phenyl-3-H-1, 5-benzodiazepine in 98% yield:1H NMR(400MHz,CDCl3)δ7.97(ddd,J＝7.7,4.9,2.0Hz,4H),7.62(dtd,J＝7.5,3.5,1.8Hz,2H),7.43(dd,J＝5.2,2.0Hz,3H),7.35(dd,J＝6.2,3.5Hz,2H),7.09(t,J＝8.6Hz,2H)；13C NMR(101MHz,CDCl3)δ165.55,163.05,153.95,152.78,140.72,140.59,137.22,133.58,133.55,130.74,130.37,130.28,128.79,128.72,128.18,128.14,125.56,115.87,115.66,34.94.
example 3
Preparing 2- (4-chlorphenyl) -4-phenyl-3-H-1, 5-benzodiazepine with the structural formula
In this example, example 1 was replaced by equimolar amounts of 1- (4-chlorophenyl) -4-phenyl-3-butyn-2-oneThe other steps of the 1, 4-diphenyl-3-butyn-2-one used in (1) were the same as in example 1 to give 2- (4-chlorophenyl) -4-phenyl-3-H-1, 5-benzodiazepine in 98% yield, and the product had spectral data as follows:1H NMR(400MHz,CDCl3)δ7.96(dd,J＝7.5,2.3Hz,2H),7.91(d,J＝8.6Hz,2H),7.65-7.57(m,2H),7.46-7.41(m,3H),7.39(s,1H),7.38-7.32(m,3H)；13C NMR(101MHz,CDCl3)δ153.90,152.68,140.76,140.47,137.15,136.91,135.70,130.78,129.45,128.95,128.80,128.73,128.16,125.69,125.58,34.82.
example 4
Preparation of 2- (4-methoxyphenyl) -4-phenyl-3-H-1, 5-benzodiazepine with the following structural formula
In this example, the equimolar 1-phenyl-4- (4-methoxyphenyl) -3-butyn-2-one was used instead of the 1, 4-diphenyl-3-butyn-2-one used in example 1, and the other procedure was the same as in example 1 to obtain 2- (4-methoxyphenyl) -4-phenyl-3-H-1, 5-benzodiazepine in 98% yield:1H NMR(400MHz,CDCl3)δ7.85(dd,J＝9.6,6.4Hz,4H),7.56-7.44(m,2H),7.34-7.26(m,3H),7.26-7.17(m,2H),6.80(d,J＝8.7Hz,2H),3.70(s,3H)；13C NMR(101MHz,CDCl3)δ161.69,154.31,153.59,140.69,137.44,130.58,130.00,129.94,128.79,128.72,128.14,125.46,125.12,114.07,55.40,34.79.
example 5
Preparation of 2- (4-methylphenyl) -4-phenyl-3-H-1, 5-benzodiazepine with the structural formula
In this example, 2- (4-methylphenyl) -4-phenyl-3-H-1, 5-benzene was obtained by replacing 1, 4-diphenyl-3-butyn-2-one used in example 1 with equimolar 1- (4-methylphenyl) -4-phenyl-3-butyn-2-one and repeating the same procedure as in example 1Diazepine in 99% yield and the product has the following spectral data:1H NMR(400MHz,CDCl3)δ7.82(dd,J＝6.7,3.0Hz,2H),7.72(d,J＝8.2Hz,2H),7.48(dt,J＝5.8,2.2Hz,2H),7.26-7.21(m,3H),7.21-7.15(m,2H),7.04(d,J＝8.0Hz,2H),2.18(s,3H)；13C NMR(101MHz,CDCl3)δ153.14,152.96,139.90,139.82,139.66,136.27,133.44,129.45,128.33,127.67,127.64,127.56,127.10,127.05,124.31,124.16,33.69,20.28.
example 6
Preparation of 2, 4-diphenyl-7-methyl-3-H-1, 5-benzodiazepine with structural formula
In this example, the o-phenylenediamine used in example 1 was replaced with an equimolar amount of 4-methyl-2-aminoaniline, and the other steps were the same as in example 1 to obtain 2, 4-diphenyl-7-methyl-3-H-1, 5-benzodiazepine in a yield of 99%, and the product had the following spectral data:1H NMR(400MHz,CDCl3)δ8.01-7.94(m,4H),7.53(d,J＝8.2Hz,1H),7.45-7.43(m,1H),7.43-7.40(m,5H),7.18(dd,J＝8.3,2.0Hz,1H),2.48(s,3H)；13C NMR(101MHz,CDCl3)δ153.81,153.35,140.56,138.58,137.48,137.39,135.37,130.56,130.47,128.70,128.68,128.61,128.14,128.09,126.93,35.03,21.17.
example 7
Preparing 2, 4-diphenyl-6-methyl-3-H-1, 5-benzodiazepine with the structural formula
In this example, the o-phenylenediamine used in example 1 was replaced with an equimolar amount of 3-methyl-2-aminoaniline, and the other steps were the same as in example 1 to obtain 2, 4-diphenyl-6-methyl-3-H-1, 5-benzodiazepine in 98% yield, and the product had the following spectral data:1H NMR(400MHz,CDCl3)δ8.04(dd,J＝6.8,3.0Hz,2H),8.00(dd,J＝6.7,3.1Hz,2H),7.54-7.48(m,1H),7.47-7.43(m,3H),7.43-7.38(m,3H),7.32-7.25(m,2H),2.60(s,3H)；13C NMR(101MHz,CDCl3)δ153.87,151.79,140.49,139.13,137.47,136.33,130.54,130.42,128.74,128.65,128.29,128.10,126.57,125.10,35.00,18.72.
example 8
Preparing 2, 4-diphenyl-7, 8-dibromo-3-H-1, 5-benzodiazepine with the structural formula
In this example, the o-phenylenediamine used in example 1 was replaced with an equimolar amount of 4, 5-dibromoo-phenylenediamine, and the other steps were the same as in example 1 to obtain 2, 4-diphenyl-7, 8-dibromo-3-H-1, 5-benzodiazepine in a yield of 96%, and the product had the following spectral data:1H NMR(400MHz,CDCl3)δ7.89-7.85(m,4H),7.79(s,2H),7.38-7.31(m,6H)；13C NMR(101MHz,CDCl3)δ155.52,140.66,136.71,133.05,131.18,128.82,128.25,120.58,35.16.
example 9
In this example, 2, 4-diphenyl-3-H-1, 5-benzodiazepine was obtained in 86% yield by replacing isophthalic acid used in example 1 with 2-hydroxynicotinic acid in an equimolar amount and performing the same procedure as in example 1.
Example 10
In this example, 2, 4-diphenyl-3-H-1, 5-benzodiazepine was obtained in 81% yield by replacing isophthalic acid used in example 1 with an equimolar amount of salicylic acid and by following the same procedure as in example 1.
Example 11
In this example, the ethanol used in example 1 was replaced with an equal volume of methanol, and the other steps were the same as in example 1, to obtain 2, 4-diphenyl-3-H-1, 5-benzodiazepine in 87% yield.
Claims (6)
1. A method for preparing benzodiazepine compounds by using dichlorotitanocene as a catalyst is characterized by comprising the following steps: adding a compound shown in a formula I and an o-phenylenediamine compound shown in a formula II into an organic solvent, adding titanocene dichloride and a ligand, reacting for 6-24 hours at room temperature, and separating and purifying a product to obtain a benzodiazepine compound shown in a formula III;
in the formula R1And R2Each independently represents phenyl, C1～C4Alkyl-substituted phenyl, C1～C4Any one of alkoxy substituted phenyl, halogenated phenyl, trifluoromethyl substituted phenyl and nitro substituted phenyl; r3、R4、R5、R6Each independent representative H, C1～C4Alkyl radical, C1～C4Any one of alkoxy, F, Cl and Br;
the organic solvent is any one of ethanol and methanol;
the ligand is any one of isophthalic acid, 2-hydroxynicotinic acid and salicylic acid.
2. The method for preparing benzodiazepine compounds by titanium dichloride catalysis according to claim 1, characterized in that: the organic solvent is ethanol.
3. The method for preparing benzodiazepine compounds by titanium dichloride catalysis according to claim 1, characterized in that: the ligand is isophthalic acid.
4. The method for preparing benzodiazepine compounds by titanium dichloride catalysis according to claim 1, characterized in that: the molar ratio of the compound shown in the formula I to the o-phenylenediamine compound is 1: 1.1-1.5.
5. The method for preparing benzodiazepine compounds by titanium dichloride catalysis according to claim 1, characterized in that: the addition amount of the titanocene dichloride is 1 to 3 percent of the molar weight of the compound in the formula I.
6. The method for preparing benzodiazepine compounds by titanium dichloride catalysis according to claim 1, characterized in that: the addition amount of the ligand is 2 to 6 percent of the molar weight of the compound in the formula I.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1317475A (en) * | 1969-06-11 | 1973-05-16 | Boehringer Sohn Ingelheim | Benzodiazepines the preparation thereof and compositions containing the same |
| GB1460936A (en) * | 1974-10-01 | 1977-01-06 | Beecham Group Ltd | Benzodiazepines |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1317475A (en) * | 1969-06-11 | 1973-05-16 | Boehringer Sohn Ingelheim | Benzodiazepines the preparation thereof and compositions containing the same |
| GB1460936A (en) * | 1974-10-01 | 1977-01-06 | Beecham Group Ltd | Benzodiazepines |
Non-Patent Citations (2)
| Title |
|---|
| Mingming Yang等.A sustainable water-tolerant catalyst with enhanced Lewis acidity:Dual activation of Cp2TiCl2 via ligand and solvent.《Molecular Catalysis》.2020,第498卷第111247（1-7）页. * |
| 庄梦媛 等.茂钛Lewis酸/Bronsted酸协同催化合成1,5-苯二氮卓类物质.《2018年中西部地区无机化学化工学术研讨会会议论文集》.2018, * |
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