CN114394933B - Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid - Google Patents
Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid Download PDFInfo
- Publication number
- CN114394933B CN114394933B CN202210018958.8A CN202210018958A CN114394933B CN 114394933 B CN114394933 B CN 114394933B CN 202210018958 A CN202210018958 A CN 202210018958A CN 114394933 B CN114394933 B CN 114394933B
- Authority
- CN
- China
- Prior art keywords
- product
- dibenzo
- azo
- dihydro
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, which comprises the following steps: s10, under the action of a first catalyst, coupling a raw material A and trimethylsilyl acetylene to obtain 2-trimethylsilyl ethynyl benzaldehyde; s20, mixing the 2-trimethylsilicoethynyl benzaldehyde with the raw material B, and carrying out reductive amination reaction to obtain a product C; s30, carrying out trimethyl silicon base removal treatment on the product C to obtain a product D; s40, under the action of a second catalyst, carrying out intramolecular coupling reaction on the product D to obtain aza-diphenyl-cyclooctyne; s50, mixing the aza-diphenyl octyne with succinic anhydride under alkaline condition, and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid. The scheme of the invention has the advantages of short synthetic route, low temperature requirement of all reaction operations, no need of active reagent, small potential safety hazard, simple operation, easily obtained raw materials and industrialization potential, and can be carried out at the temperature of below 100 ℃.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid.
Background
The Diphenylazacyclooctyne (DBCO) derivatives are widely used raw materials at present. Wherein 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid (dbcooh) is a reactant for synthesizing advanced polyester dendrimer, and can also be used for preparing modularized, plasmin-sensitive, clickable poly (ethylene glycol) -heparin-lamitin microsphere system to generate growth factor gradient in peripheral nerve regeneration, which is a common medical intermediate.
At present, two methods for constructing DBCOCOOH are mainly reported by van Delft and Popik respectively: in 2014 van Delft and colleagues reported that diphenylalkyne is built through Sonogashira cross-coupling reaction, cis-alkene is obtained through hydrogenation, key intermediate is obtained through oxidative deprotection and reductive amination, acid is obtained through amidation and hydrolysis, and final product DBCOCOOH is obtained through bromination and elimination reaction, so that the method has long synthetic route and complex operation for building alkyne bond; in the same year, popik reports that 5-dibenzosuberone is used as an initial substrate to react with hydroxylamine to generate oxime, then Beckmann rearrangement and lithium aluminum hydride reduction are carried out to obtain a key intermediate, and finally a product DBCOCOOH is obtained through similar reaction conditions. Furthermore, neither of these methods can achieve production on the order of hundred grams or more.
Disclosure of Invention
The invention mainly aims to provide a synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, and aims to provide a synthesis method with short synthesis route, low reaction condition requirement and simple operation.
In order to achieve the above object, the present invention provides a method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, the method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid comprising the steps of:
s10, under the action of a first catalyst, coupling a raw material A and trimethylsilyl acetylene to obtain 2-trimethylsilyl ethynyl benzaldehyde;
s20, mixing the 2-trimethylsilicoethynyl benzaldehyde with the raw material B, and carrying out reductive amination reaction to obtain a product C;
s30, carrying out trimethyl silicon base removal treatment on the product C to obtain a product D;
s40, under the action of a second catalyst, carrying out intramolecular coupling reaction on the product D to obtain aza-diphenyl-cyclooctyne;
s50, mixing the aza-diphenyl octyne with succinic anhydride under alkaline condition, and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid;
wherein the raw material A has a structural formula shown in a formula (I) and R 1 Independently selected from any one of Cl, br, I and OTf; the raw material B has a structural formula shown as a formula (II) and R 2 Independently selected from Cl,Any one of Br, I and OTf; the product C has a structural formula shown in a formula (III); the product D has a structural formula shown in a formula (IV); the first catalyst comprises a palladium catalyst and a copper catalyst; the second catalyst comprises a palladium catalyst and a copper catalyst;
formula (I):
formula (II):
formula (iii):
formula (iv):
optionally, the copper catalyst comprises cuprous iodide, cuprous chloride or cuprous bromide; and/or the number of the groups of groups,
the palladium catalyst comprises any one of tetra (triphenylphosphine) palladium, diphenylphosphine palladium dichloride, palladium acetate, 1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-dibenzylideneacetone palladium.
Optionally, in step S10, the molar ratio of the raw material a, the trimethylsilylacetylene, and the palladium catalyst and the copper catalyst in the first catalyst is 1: (0.8-3): (0.005-0.2): (0.005-0.5); and/or the number of the groups of groups,
the coupling reaction is carried out at 15-120 ℃; and/or the number of the groups of groups,
the coupling reaction is carried out in a protective atmosphere.
Optionally, step S10 includes:
mixing the raw material A, a first catalyst and a solvent, adding alkali, uniformly stirring, adding trimethylsilylacetylene, and stirring to perform a coupling reaction to obtain 2-trimethylsilylethynyl benzaldehyde;
wherein the mol ratio of the raw material A to the alkali is 1 (1-10).
Alternatively, in step S20, the molar ratio of the 2-trimethylsilylethynylbenzaldehyde to the starting material B is 1: (0.8-2); and/or the number of the groups of groups,
the reaction temperature of the reductive amination reaction is-10 ℃ to 40 ℃.
Optionally, step S30 includes:
and dissolving the product C in methanol, adding potassium carbonate, and reacting to obtain a product D.
Optionally, in step S40, the molar ratio of the product D to the second catalyst is 1 (0.005-0.1).
Alternatively, the intramolecular coupling reaction is carried out in a shielding gas and the concentration of the corresponding product D is 0.1 to 0.01 mole per liter of shielding gas.
Optionally, in step S50, the molar ratio of the azadiphenyl octyne to the succinic anhydride is 1: (0.8-3); and/or the number of the groups of groups,
step S50 includes:
dissolving the aza-diphenyl octyne and succinic anhydride in a solvent, adding alkali, stirring at the temperature of 10-40 ℃ and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, wherein the molar ratio of the aza-diphenyl octyne to the alkali is 1: (0.8-3).
Optionally, the base includes any one of pyridine, N-dimethylaminopyridine, potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine.
In the technical scheme provided by the invention, 2-halobenzaldehyde or 2-OTf benzaldehyde and trimethylsilyl acetylene are used as starting materials, aza-diphenyl ring octyne (DBCO) is built through intramolecular Sonogashira cross-coupling reaction, and then 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid (DBCOCOOH) is built through a DBCO and succinic anhydride one-step method, so that the synthetic route is short, the requirements of all reaction operations on temperature are low, the reaction can be carried out at-10 ℃ to 100 ℃, active reagents are not needed, the potential safety hazard is small, the operation is simple, the raw materials are easy to obtain, and the industrialized potential is realized.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. In addition, the meaning of "and/or" as it appears throughout includes three parallel schemes, for example "A and/or B", including the A scheme, or the B scheme, or the scheme where A and B are satisfied simultaneously. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be regarded as not exist and not within the protection scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
At present, two methods for constructing DBCOCOOH are mainly reported by van Delft and Popik respectively:
in 2014 van Delft and his colleagues reported the construction of diphenyne 1c by Sonogashira cross-coupling reaction, followed by hydrogenation to give cis-alkene 1e, followed by oxidative deprotection and reductive amination to give key intermediate 1 g, followed by amidation, hydrolysis to give acid 1i, and finally bromination and elimination of 1i to give the final product DBCOCOOH, the detailed reaction scheme of which is shown below.
van Delft method
The method has long synthetic route and complex operation for constructing the alkyne bond.
In the same year, popik reports that oxime 2b is produced by reacting 5-dibenzosuberone as an initial substrate with hydroxylamine, then 1 g of key intermediate is obtained by Beckmann rearrangement and lithium aluminum hydride reduction, and finally the product DBCOCOOH is obtained by similar reaction conditions, wherein the reaction route is as follows:
popik method
This method requires the use of a very reactive reagent such as lithium aluminum hydride or diisobutyl aluminum hydride, and is also complicated in the construction of an acetylenic bond.
Both methods are not suitable for industrial scale-up production.
In view of this, the invention provides a synthesis method of 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, which has the advantages of short synthesis route, simple operation, easy achievement of reaction conditions, no potential safety hazard and small quantity of raw materials.
The synthetic route of the 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid is as follows:
in the technical scheme provided by the invention, 2-halobenzaldehyde or 2-OTf benzaldehyde and trimethylsilyl acetylene are used as starting materials, aza-diphenyl cyclooctyne (DBCO) is built through intramolecular Sonogashira cross-coupling reaction, and then 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid (DBCOCOOH) is built through a one-step method of DBCO and succinic anhydride, so that the synthetic route is short, the requirements of all reaction operations on temperature are low, the reaction operations can be carried out at a temperature below-10-100 ℃, active reagents are not needed, the potential safety hazard is small, the operation is simple, the raw materials are easy to obtain, and the industrial potential is realized.
Wherein TMS refers to trimethylsilyl group, OTf refers to trifluoromethanesulfonyl group.
Specifically, the synthesis method of the 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid comprises the following steps:
step S10, under the action of a first catalyst, coupling the raw material A and trimethylsilyl acetylene to obtain 2-trimethylsilyl ethynyl benzaldehyde.
Wherein the raw material A has a structural formula shown in a formula (I):
formula (I):
wherein R is 1 And is independently selected from any one of Cl, br, I and OTf, namely the raw material A is any one of 2-chlorobenzaldehyde, 2-bromobenzaldehyde, 2-iodobenzaldehyde and 2-trifluoromethanesulfonyl benzaldehyde.
The first catalyst includes a palladium catalyst and a copper catalyst. The invention is not limited to specific types of palladium catalysts/copper catalysts, and takes palladium catalysts as an example, the main active components comprise palladium, and substances with catalytic activity can be adopted, so that the common palladium catalysts in the market belong to the protection scope of the invention. Further, the palladium catalyst of the present invention preferably comprises any one of tetrakis (triphenylphosphine) palladium, diphenylphosphine palladium dichloride, palladium acetate, 1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-dibenzylideneacetone palladium. Further, the copper catalyst includes cuprous iodide, cuprous chloride, or cuprous bromide.
In addition, in this example, the molar ratio of the raw material a, the trimethylsilylacetylene, and the palladium catalyst and the copper catalyst in the first catalyst was 1: (0.8-3): (0.005-0.2): (0.005-0.5); the coupling reaction is carried out at 15-120 ℃; the coupling reaction is carried out in a protective atmosphere which can be nitrogen, helium and the like, can avoid oxidation in the protective atmosphere, leads to the generation of byproducts and is beneficial to improving the purity and the yield of the product.
In specific implementation, step S10 includes:
step S11, mixing the raw material A, a first catalyst and a solvent, adding alkali, uniformly stirring, adding trimethylsilylacetylene, and stirring to perform a coupling reaction to obtain 2-trimethylsilylethynyl benzaldehyde;
wherein the mol ratio of the raw material A to the alkali is 1 (1-10).
In addition, the specific kind of the solvent is not limited to the present invention, and may be any common solvent which can dissolve the reaction substance and the product and does not participate in the reaction, for example, tetrahydrofuran. Likewise, the particular type of base is not limiting and may be any of the usual basic materials, preferably an amine, such as triethylamine.
Step S20, mixing the 2-trimethylsilicoethynyl benzaldehyde with the raw material B, and carrying out reductive amination reaction to obtain a product C.
Wherein the raw material B has a structural formula shown as a formula (II):
formula (II):
wherein R is 2 And is independently selected from any one of Cl, br, I and OTf, namely, the raw material B can be any one of 2-chloroaniline, 2-bromoaniline, 2-iodoaniline and 2-trifluoromethanesulfonyl aniline.
Wherein, the product C has a structural formula shown as a formula (III):
formula (iii):
wherein R is 2 As mentioned above, details are not given here.
In the step, the molar ratio of the 2-trimethylsilicoethynyl benzaldehyde to the raw material B is 1: (0.8-2); the reaction temperature of the reductive amination reaction is-10 ℃ to 40 ℃.
The reaction in the step is reductive amination, and in specific implementation, the 2-trimethylsilicoethynyl benzaldehyde and the raw material B can be mixed, then a reducing agent is added, and the reaction is completed under the promotion of the reducing agent, so that a reduction product C is obtained. Wherein the reducing agent can be sodium borohydride, sodium triacetyl borohydride or sodium cyanoborohydride. In practice, an acid medium may also be added to promote the reaction, and in particular, the acid medium may be acetic acid.
And step S30, carrying out trimethyl silicon base removal treatment on the product C to obtain a product D.
The invention is not limited to a specific method for removing trimethylsilyl group, and can be used in a potassium carbonate-methanol system or a citric acid/methanol/THF system.
Wherein the product D has a structural formula shown in a formula (IV):
formula (iv):
in specific implementation, step S30 may include the following steps:
step S31, dissolving the product C in methanol, adding potassium carbonate, and reacting to obtain a product D.
The addition amount of methanol and potassium carbonate can be referred to the conventional method for removing trimethylsilyl group from potassium carbonate-methanol system in the art, and will not be described in detail herein.
And step S40, under the action of a second catalyst, the product D is subjected to intramolecular coupling reaction to obtain the aza-diphenyl cyclooctyne.
Wherein the second catalyst comprises a palladium catalyst and a copper catalyst. The invention is not limited to specific types of palladium catalysts/copper catalysts, and takes palladium catalysts as an example, the main active components comprise palladium, and substances with catalytic activity can be adopted, so that the common palladium catalysts in the market belong to the protection scope of the invention. Further, the palladium catalyst of the present invention preferably comprises any one of tetrakis (triphenylphosphine) palladium, diphenylphosphine palladium dichloride, palladium acetate, 1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-dibenzylideneacetone palladium. Further, the copper catalyst includes cuprous iodide, cuprous chloride, or cuprous bromide.
It will be appreciated that the specific choice of the first catalyst and the second catalyst are independent of each other, and the two catalysts may be the same type of catalyst, or may be different types of catalysts, which is not a limitation of the present invention.
In this step, the molar ratio of the product D to the second catalyst is 1 (0.005 to 0.1); the intramolecular coupling reaction is carried out in a protective gas, the concentration of the corresponding product D in each liter of the protective gas is 0.1-0.01 mole, the protective atmosphere can be nitrogen, helium and the like, oxidation can be avoided in the protective atmosphere, by-products are generated, and the purity and the yield of the product are improved. The reaction temperature may be 15℃to 120℃and is preferably room temperature, i.e.15℃to 30 ℃.
Step S50, mixing the aza-diphenyl octyne with succinic anhydride under alkaline condition, and reacting to obtain 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid.
Wherein, the mol ratio of the aza-diphenyl octyne to the succinic anhydride is 1: (0.8-3).
In specific implementation, step S50 includes:
step S51, dissolving the aza-diphenyl octyne and succinic anhydride in a solvent, adding alkali, stirring at the temperature of 10-40 ℃ and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, wherein the molar ratio of the aza-diphenyl octyne to the alkali is 1: (0.8-3).
Wherein the base comprises any one of pyridine, N-dimethylaminopyridine, potassium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The method has short synthetic route and easy achievement of reaction conditions.
The following description of the embodiments of the present invention will be presented in further detail with reference to the examples, which should be understood as being merely illustrative of the present invention and not limiting.
The room temperature referred to in the examples below is 15 to 25℃and is not constant.
Example 1
The synthetic route for this example is as follows:
into a 500 ml round bottom reaction flask was charged 9.25 g of 2-bromobenzaldehyde 4a (about 25 mmol), 2.5 mmol of diphenylphosphine palladium dichloride, 2.5 mmol of cuprous iodide and 200 ml of tetrahydrofuran. The air in the bottle was replaced three times with nitrogen. 150 mmol of triethylamine are then added. After stirring for 10 minutes, 75 mmole of trimethylsilylacetylene was added and stirred overnight at room temperature under nitrogen. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulphate and then spin-dried and passed through a column to give 9.5 g of product 4b.
1 H NMR(500MHz,CDCl 3 )δ0.29(9H,s),7.40-7.47(1H,m),7.51-7.63(2H,m),7.91(1H,d,J＝7.3Hz),10.56(1H,s).
4.9 mmol of 4b,4.9 mmol of 2-iodoaniline 4c and 0.28 ml of acetic acid are dissolved in 15 ml of dichloromethane. 1.41 g of sodium triacetoxyborohydride are added in portions. The mixture was stirred at room temperature for 16 hours and then quenched by the addition of 20 ml of 1M (i.e. mol/L) sodium hydroxide solution. The mixture was extracted three times with dichloromethane and the organic phases were combined. Then dried over anhydrous magnesium sulfate and spin-dried over silica gel column to give 1.3 g of product 4d.
1 H NMR(400MHz,CDCl 3 )δ0.26(9H,s),4.57(2H,d,J＝5.6Hz),4.79(1H,t,J＝5.6Hz),6.45(1H,td,J＝7.5,1.3Hz),6.55(1H,dd,J＝8.1,1.2Hz),7.13-7.19(1H,m),7.23(1H,dd,J＝7.3,1.2Hz),7.28-7.32(1H,m),7.33-7.37(1H,m),7.51(1H,dd,J＝7.6,1.0Hz),7.68(1H,dd,J＝7.8,1.5Hz).
4.2 mmol of starting material 4d are dissolved in 35 ml of methanol. Then 2.1 mmole of potassium carbonate was added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction solution was then filtered and spin-dried over a silica gel column to give 1.05 g of product 4e.
1 H NMR(500MHz,CDCl 3 )δ3.41(1H,s),4.60(2H,d,J＝5.4Hz),4.81(1H,br.s.),6.45(1H,t,J＝7.6Hz),6.52(1H,d,J＝8.2Hz),7.13-7.18(1H,m),7.22-7.27(1H,m),7.30-7.35(1H,m),7.36-7.40(1H,m),7.55(1H,d,J＝7.6Hz),7.69(1H,d,J＝7.7Hz).
Into a 100 ml round bottom reaction flask was added 2.1 mmol 4e,0.042 mmol diphenylphosphine palladium dichloride, 0.042 mmol cuprous iodide and 30 ml tetrahydrofuran. The nitrogen was replaced three times. Then 6.3 mmol of triethylamine was added and stirred overnight protected from light under nitrogen (the nitrogen concentration was controlled in accordance with the concentration of the product D in each liter of shielding gas being 0.1 to 0.01 mol). The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulphate and then spin-dried and passed through a column to give 0.15 g of product 4f.
1 H NMR(500MHz,CDCl 3 )δ4.63(2H,d,J＝5.8Hz),4.84(1H,brs.),6.45(1H,t,J＝7.6Hz),6.51(1H,d,J＝8.2Hz),7.15(1H,t,J＝7.7Hz),7.24-7.29(1H,m),7.33-7.37(1H,m),7.38-7.41(1H,m),7.58(1H,d,J＝7.4Hz),7.68(1H,dd,J＝7.7,0.9Hz).
8.0 mmol of starting material 4f and 24.0 mmol of succinic anhydride were dissolved in 50 ml of dichloromethane, then 24 mmol of pyridine were slowly added dropwise and stirred at room temperature for 12 hours. The reaction was then quenched with 10 ml of 1M hydrochloric acid. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried over silica gel column to give 4.29 g of product DBCOCOOH.
1 H NMR(500MHz,DMSO-d 6 )δ1.78(2H,dt,J＝16.6,6.4Hz),2.14-2.23(1H,m),2.25-2.34(1H,m),2.54-2.64(1H,m),3.64(1H,s),5.03(2H,d,J＝14.0Hz),7.26-7.31(1H,m),7.34(1H,t,J＝7.3Hz),7.36-7.40(1H,m),7.44-7.53(3H,m),7.62(1H,d,J＝7.3Hz),7.66(1H,d,J＝7.3Hz),11.97(1H,br.s.)
Example 2
Into a 500 ml round bottom reaction flask was charged 5.21 g of 2-OTf benzaldehyde (about 25 mmol), 0.125 mmol of 1,1' -bis-diphenylphosphino ferrocene palladium dichloride, 0.125 mmol of cuprous iodide and 200 ml of tetrahydrofuran. The air in the bottle was replaced three times with nitrogen. 25 mmoles of triethylamine are then added. After stirring for 10 minutes, 20 mmol of trimethylsilylacetylene was added and stirred overnight at 25℃under nitrogen. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulfate and then spin dried and passed through a column to give 2-trimethylsilylethynylbenzaldehyde.
4.9 mmol of 2-trimethylsilylethynylbenzaldehyde, 3.92 mmol of 2-trifluoromethanesulfonyl-aniline and 0.28 ml of acetic acid are dissolved in 15 ml of dichloromethane. 1.41 g of sodium borohydride are added in portions. The mixture was stirred at-10℃for 16 hours and quenched by the addition of 20 ml of 1M sodium hydroxide solution. The mixture was extracted three times with dichloromethane and the organic phases were combined. Then dried with anhydrous magnesium sulfate, and spin-dried through a silica gel column to obtain a product C-1.
4.2 mmol of product C-1 are dissolved in 35 ml of methanol. Then 2.1 mmole of potassium carbonate was added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction solution was then filtered and spin-dried over a silica gel column to give the product D-1.
Into a 100 ml round bottom reaction flask was charged 2.1 mmol of product D-1,0.005 mmol of 1,1' -bis-diphenylphosphino ferrocene palladium dichloride, 0.005 mmol of cuprous iodide and 30 ml of tetrahydrofuran. The nitrogen was replaced three times. Then 6.3 mmol of triethylamine was added and stirred overnight protected from light under nitrogen (the nitrogen concentration was controlled in accordance with the concentration of the product D in each liter of shielding gas being 0.1 to 0.01 mol). The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulphate and then spin-dried and passed through a column to give DBCO.
8 mmol of DBCO and 0.64 mmol of succinic anhydride were dissolved in 50 ml of dichloromethane, then 6.4 mmol of triethylamine was slowly added dropwise and stirred at 10℃for 12 hours. The reaction was then quenched with 10 ml of 1M hydrochloric acid. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried over silica gel to give 4.08 g of the product, which was identified as DBCOCOOH by nuclear magnetic resonance spectroscopy.
Wherein, the structural formula of the product C-1 is as follows:
the structural formula of the product D-1 is as follows:
example 3
Into a 500 ml round bottom reaction flask was charged 3.51 g 2-chlorobenzaldehyde (about 25 mmol), 5 mmol tetrakis (triphenylphosphine) palladium, 5 mmol cuprous bromide and 200 ml tetrahydrofuran. The air in the bottle was replaced three times with nitrogen. 250 mmoles of triethylamine are then added. After stirring for 10 minutes, 25 mmole of trimethylsilylacetylene was added and stirred overnight at 15℃under nitrogen. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulfate and then spin dried and passed through a column to give 2-trimethylsilylethynylbenzaldehyde.
4.9 mmol of 2-trimethylsilylethynylbenzaldehyde, 9.8 mmol of 2-chloroaniline and 0.28 ml of acetic acid were dissolved in 15 ml of dichloromethane. 1.41 g of sodium triacetoxyborohydride are added in portions. The mixture was stirred at 25℃for 16 hours and quenched by the addition of 20 ml of 1M sodium hydroxide solution. The mixture was extracted three times with dichloromethane and the organic phases were combined. Then dried with anhydrous magnesium sulfate, and spin-dried through a silica gel column to obtain a product C-2.
4.2 mmol of product C-2 are dissolved in 35 ml of methanol. Then 2.1 mmole of potassium carbonate was added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction solution was then filtered and spin-dried over a silica gel column to give the product D-2.
Into a 100 ml round bottom reaction flask was charged 2.1 mmol of product D-2,0.105 mmol of tetrakis (triphenylphosphine) palladium, 0.105 mmol of cuprous chloride and 30 ml of tetrahydrofuran. The nitrogen was replaced three times. Then 6.3 mmol of triethylamine was added and stirred overnight protected from light under nitrogen (the nitrogen concentration was controlled in accordance with the concentration of the product D in each liter of shielding gas being 0.1 to 0.01 mol). The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulphate and then spin-dried and passed through a column to give DBCO.
8 mM DBCO and 8 mM succinic anhydride were dissolved in 50 ml of methylene chloride, followed by slow dropwise addition of 8 mM N, N-dimethylaminopyridine and stirring at 40℃for 12 hours. The reaction was then quenched with 10 ml of 1M hydrochloric acid. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried over silica gel to give 4.16 g of the product, which was identified as DBCOCOOH by nuclear magnetic resonance spectroscopy.
Wherein, the structural formula of the product C-2 is as follows:
the structural formula of the product D-2 is as follows:
example 4
Into a 500 ml round bottom reaction flask was added 5.8 g of 2-iodobenzaldehyde (about 25 mmol), 2.5 mmol of palladium bis dibenzylidene acetonide, 2.5 mmol of cuprous chloride and 200 ml of tetrahydrofuran. The air in the bottle was replaced three times with nitrogen. 125 mmoles of triethylamine are then added. After stirring for 10 minutes, 75 mmole of trimethylsilylacetylene was added and stirred overnight at 120℃under nitrogen. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulfate and then spin dried and passed through a column to give 2-trimethylsilylethynylbenzaldehyde.
4.9 mmol of 2-trimethylsilylethynylbenzaldehyde, 4.9 mmol of 2-bromoaniline and 0.28 ml of acetic acid are dissolved in 15 ml of dichloromethane. 1.41 g of sodium triacetoxyborohydride are added in portions. The mixture was stirred at 40℃for 16 hours and quenched by the addition of 20 ml of 1M sodium hydroxide solution. The mixture was extracted three times with dichloromethane and the organic phases were combined. Then dried with anhydrous magnesium sulfate, and spin-dried through a silica gel column to obtain a product C-3.
4.2 mmol of product C-3 are dissolved in 35 ml of methanol. Then 2.1 mmole of potassium carbonate was added. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction solution was then filtered and spin-dried over a silica gel column to give the product D-3.
Into a 100 ml round bottom reaction flask was added 2.1 mmol of product D-3,0.052 mmol of palladium acetate, 0.052 mmol of cuprous bromide and 30 ml of tetrahydrofuran. The nitrogen was replaced three times. Then 6.3 mmol of triethylamine was added and stirred overnight protected from light under nitrogen (the nitrogen concentration was controlled in accordance with the concentration of the product D in each liter of shielding gas being 0.1 to 0.01 mol). The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases are then combined and washed once with saturated brine, dried over sodium sulphate and then spin-dried and passed through a column to give DBCO.
8 mmol of DBCO and 24 mmol of succinic anhydride were dissolved in 50 ml of dichloromethane, then 24 mmol of diisopropylethylamine was slowly added dropwise and stirred at room temperature for 12 hours. The reaction was then quenched with 10 ml of 1M hydrochloric acid. The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried over silica gel to give 4.01 g of the product, which was identified as DBCOCOOH by nuclear magnetic resonance spectroscopy.
Wherein, the structural formula of the product C-2 is as follows:
the structural formula of the product D-2 is as follows:
the foregoing is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention, but various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid, comprising the steps of:
s10, under the action of a first catalyst, coupling a raw material A and trimethylsilyl acetylene to obtain 2-trimethylsilyl ethynyl benzaldehyde;
s20, mixing the 2-trimethylsilicoethynyl benzaldehyde with the raw material B, and carrying out reductive amination reaction to obtain a product C;
s30, carrying out trimethyl silicon base removal treatment on the product C to obtain a product D;
s40, under the action of a second catalyst, carrying out intramolecular coupling reaction on the product D to obtain aza-diphenyl-cyclooctyne;
s50, mixing the aza-diphenyl octyne with succinic anhydride under alkaline conditions, and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid;
wherein the raw material A has a structural formula shown in a formula (I) and R 1 Independently selected from any one of Cl, br, I and OTf; the raw material B has a structural formula shown as a formula (II) and R 2 Independently selected from any one of Cl, br, I and OTf; the product C has a structural formula shown in a formula (III); the product D has a structural formula shown in a formula (IV); the first catalyst comprises a palladium catalyst and a copper catalyst; the second catalyst comprises a palladium catalyst and a copper catalyst;
formula (I):
formula (II):
formula (iii):
formula (iv):
2. the method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein the copper catalyst comprises cuprous iodide, cuprous chloride or cuprous bromide; and/or the number of the groups of groups,
the palladium catalyst comprises any one of tetra (triphenylphosphine) palladium, diphenylphosphine palladium dichloride, palladium acetate, 1' -bis-diphenylphosphine ferrocene palladium dichloride and bis-dibenzylideneacetone palladium.
3. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein in step S10, the molar ratio of the raw material a, the trimethylsilylacetylene, and the palladium catalyst and copper catalyst in the first catalyst is 1: (0.8-3): (0.005-0.2): (0.005-0.5); and/or the number of the groups of groups,
the coupling reaction is carried out at 15-120 ℃; and/or the number of the groups of groups,
the coupling reaction is carried out in a protective atmosphere.
4. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein step S10 comprises:
mixing the raw material A, a first catalyst and a solvent, adding alkali, uniformly stirring, adding trimethylsilylacetylene, and stirring to perform a coupling reaction to obtain 2-trimethylsilylethynyl benzaldehyde;
wherein the mol ratio of the raw material A to the alkali is 1 (1-10).
5. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein in step S20, the molar ratio of the 2-trimethylsilylethynylbenzaldehyde to the starting material B is 1: (0.8-2); and/or the number of the groups of groups,
the reaction temperature of the reductive amination reaction is-10 ℃ to 40 ℃.
6. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein step S30 comprises:
and dissolving the product C in methanol, adding potassium carbonate, and reacting to obtain a product D.
7. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein the molar ratio of the product D to the second catalyst in step S40 is 1 (0.005-0.1).
8. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein the intramolecular coupling reaction is performed in a protective gas, and the concentration of the corresponding product D is 0.1 to 0.01 mole per liter of protective gas.
9. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 1, wherein in step S50, the molar ratio of azadiphenyl octyne to succinic anhydride is 1: (0.8-3); and/or the number of the groups of groups,
step S50 includes:
dissolving the aza-diphenyl octyne and succinic anhydride in a solvent, adding alkali, stirring at the temperature of 10-40 ℃ and reacting to obtain 11, 12-dihydro-gamma-oxo-dibenzo [ [ F ] azo-5- (6H) -butyric acid, wherein the molar ratio of the aza-diphenyl octyne to the alkali is 1: (0.8-3).
10. The method for synthesizing 11, 12-dihydro- Γ -oxo-dibenzo [ F ] azo-5- (6H) -butyric acid according to claim 9, wherein the base comprises any one of pyridine, N-dimethylaminopyridine, potassium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210018958.8A CN114394933B (en) | 2022-01-07 | 2022-01-07 | Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210018958.8A CN114394933B (en) | 2022-01-07 | 2022-01-07 | Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114394933A CN114394933A (en) | 2022-04-26 |
| CN114394933B true CN114394933B (en) | 2023-08-22 |
Family
ID=81229125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210018958.8A Active CN114394933B (en) | 2022-01-07 | 2022-01-07 | Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114394933B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529898A (en) * | 2015-01-15 | 2015-04-22 | 成都丽凯手性技术有限公司 | Heterocyclic nitrogen-dibenz-cyclooctyne class compound and preparation method thereof |
| CN110291097A (en) * | 2016-11-08 | 2019-09-27 | 里珍纳龙药品有限公司 | Steroidal compounds and its protein-conjugate |
-
2022
- 2022-01-07 CN CN202210018958.8A patent/CN114394933B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529898A (en) * | 2015-01-15 | 2015-04-22 | 成都丽凯手性技术有限公司 | Heterocyclic nitrogen-dibenz-cyclooctyne class compound and preparation method thereof |
| CN110291097A (en) * | 2016-11-08 | 2019-09-27 | 里珍纳龙药品有限公司 | Steroidal compounds and its protein-conjugate |
Non-Patent Citations (1)
| Title |
|---|
| Highly Efficient Multigram Synthesis of Dibenzoazacyclooctyne (DBCO) without Chromatography;Stuart A. McNelles等;Org. Process Res. Dev.;第23卷;第2740-2745页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114394933A (en) | 2022-04-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108440330B (en) | Preparation method of doxycycline hydrochloride | |
| Vijender et al. | Amberlist-15 as heterogeneous reusable catalyst for regioselective ring opening of epoxides with amines under mild conditions | |
| CN102002066B (en) | Synthesis method of 4-acetoxyl-2-azetidinone | |
| CN102548958A (en) | Method for preparing tricyclic derivatives | |
| CN110698467A (en) | Synthetic method of engagliflozin | |
| CN114394933B (en) | Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid | |
| CN113248432A (en) | Novel method for preparing intermediate of roxasistat in high yield | |
| CN115894540A (en) | Preparation method of lithium tri-sec-butyl borohydride | |
| CN109824516B (en) | Preparation method of trans-4-hydroxycyclohexanecarboxylic acid tert-butyl ester | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN109761947B (en) | Synthesis method of functionalized benzo chromene compound | |
| JPS62192389A (en) | 1,1-dichloro-1,2,2,-trimethyl-2-phenyldisilane and production thereof | |
| CN113214119B (en) | Selective addition method of dienamine and phenylboronic acid controlled by small steric hindrance | |
| CN116217625B (en) | CNC (computer numerical control) tridentate ruthenium complex as well as preparation method and application thereof | |
| CN109265385A (en) | A kind of synthesis technology of chiral catalyst | |
| CN113004161B (en) | Preparation method of (2R, 3R) -3-methyl-3-phenylalanine | |
| CN116497082B (en) | Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method | |
| KR101251625B1 (en) | Novel manufacturing method of dutasteride using novel intermediates | |
| CN113880803B (en) | Preparation method of XPO-1 inhibitor | |
| CN110305025B (en) | Method for synthesizing benzylamine compound by imine catalytic hydrogenation | |
| CN112094234B (en) | Synthesis method of 6-phenyl-2, 3,4, 7-tetrahydro-1H-3-azepine derivative | |
| CN112142709B (en) | Synthetic method of 6-aryl-2,3,4,5-tetrahydrooxaheptin-3-alcohol derivative | |
| JPH01121268A (en) | Production of 3,5-dichloropyridine | |
| JP4617551B2 (en) | Method for producing di-t-butyl dicarbonate | |
| CN118146095A (en) | Preparation method of iloprost intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |