CN104529898B - Azepine dibenzo cyclooctyne compounds and preparation method thereof - Google Patents
Azepine dibenzo cyclooctyne compounds and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of azepine dibenzo cyclooctyne compounds and preparation method thereof; belong to organic chemical synthesis field; this structural formula of compound formula is as shown in the formula (I); the present invention is with 5 dibenzosuberenones as initiation material; end product azepine dibenzo cyclooctyne hydrochlorate, total recovery more than 73.6% has been obtained through reactions such as oximate, Beckmann rearrangement, reduction of amide, protection, addition, debrominate, deprotections.Its raw material is simple and easy to get, and convenient post-treatment easily operates, and total recovery is higher.The present invention has synthesized the azepine dibenzo cyclooctyne compounds of unsubstituted on nitrogen-atoms first, can be that the azepine dibenzo cyclooctyne compounds of band different substituents on synthetic nitrogen atom provides new method, it is difficult to the azepine dibenzo cyclooctyne compounds of band different substituents on the nitrogen-atoms of preparation with additive method especially for some, with the product of the present invention as raw material, the R base that the H above nitrogen needs can be replaced.
Description
Technical field
The present invention relates to organic chemical synthesis field, particularly relate to a kind of azepine dibenzo cyclooctyne compounds and system thereof
Preparation Method.
Background technology
The 1,3-Dipolar Cycloaddition that Cu (I) is catalyzed is because its selectivity is good, response speed is fast and high yield is by wide
General concern, is frequently used in biomedical sector, such as the synthesis of Polyethylene Glycol-protein bio conjugated body.But
In such product reacted, usually can remain a small amount of Cu (I), and the Cu of remaining (I) can be attached to the avtive spot of enzyme,
Thus cause the activity reduction of enzyme, even make enzyme inactivate, and then cell is produced toxic action.Meanwhile, Cu (I) is at aqueous environment
Under be susceptible to dismutation reaction and reaction rate declined.Therefore look for 1,3-dipole-ring new, that do not have Cu (I) to participate in add
Reaction is become to receive much concern.
In recent years, azepine dibenzo cyclooctyne compounds is due to the chemical constitution of its uniqueness and reactivity, it is easy to
Occur 1 in a mild condition with nitrine or nitrone compound, 3-dipole-diople interaction, such reaction does not participates in catalysis by metal
Reaction, but the tension force possessed by self promotes the carrying out of reaction, it is possible to achieve " click " without metal reacts.With
Time, it is fast that it still possesses reaction, good selective.Therefore, such reaction is widely used in biomedicine field, the most just
Positron emission tomography (PET), polysaccharide labelling etc..And azepine dibenzo cyclooctyne and cyclooctyne and dibenzo cyclooctyne phase
Ratio, has again the advantages such as strong, the favourable kinetics support of hydrophilic.
At present, the synthesis of azepine dibenzo cyclooctyne compounds is the most highly developed, with substituent group on nitrogen-atoms
Azepine dibenzo cyclooctyne compounds has extensively been synthesized and has been carried out a series of research, as with 5-dibenzosuberenone
Even for the multistep reaction (Synthesis, 2014,46,669) of raw material, Sonogashira with adjacent aminobenzene acetylene as raw material
Connection reaction (Chem.Commun., 2010,46,97) and the Heck reaction with adjacent iodobenzene ammonia as raw material
(Chem.Eur.J.2013,19,2150) etc..But, the synthesis azepine dibenzo cyclooctyne compounds of report is all at present
The compound of substituted base on nitrogen, and different substituent groups is required for doing from synthetic route raw material foremost, and nitrogen is former
On son, the synthesis of azepine dibenzo cyclooctyne compounds without substituent group have not been reported.
It addition, by observing its structure, we are it is found that by certain chemical means, we can be with nitrogen-atoms
On be crucial general character intermediate without the azepine dibenzo cyclooctyne compounds of substituent group, synthesize a series of nitrogen as required former
The azepine dibenzo cyclooctyne compounds of band different substituents on son, following conversion:
It is difficult to this compounds of preparation by conventional method especially for some.Therefore it provides without taking on nitrogen-atoms
The azepine dibenzo cyclooctyne compounds of Dai Ji has very important realistic meaning.
Summary of the invention
An object of the present invention, is to provide the azepine dibenzo cyclooctyne class without substituent group on a kind of nitrogen-atoms
Compound, to solve the problems referred to above.
To achieve these goals, the technical solution used in the present invention is such that a kind of azepine dibenzo cyclooctyne class
Compound, its structural formula formula as shown in the formula (I):
Wherein:
R in formula (I)1, R2For H, alkyl, halogen, R1And R2Can be the same or different；
And R1, R2For arbitrarily may replace the substituent group of position on phenyl ring.
As preferred technical scheme: R1=R2=H。
The two of the purpose of the present invention, are a kind of preparation method providing above-claimed cpd, and the technical scheme of employing is: bag
Include following steps:
(1) with 5-dibenzosuberenone as initiation material, through being condensed to yield compound shown in formula (III)；
(2) compound shown in formula (IV) is obtained through Beckmann rearrangement synthesis；
(3) compound shown in formula V is obtained through reduction synthesis；
(4) on nitrogen, protection group synthesis obtains compound shown in formula (VI) again；
(5) by obtaining compound shown in formula (VII) with bromine addition synthesis；
(6) it is then passed through debrominate and prepares compound shown in formula (VIII)；
(7) eventually pass deprotection and prepare compound shown in formula (I), i.e. azepine dibenzo cyclooctyne.
Its synthetic route is as follows:
In above-mentioned step (7), the inorganic acids such as hydrochloric acid, sulphuric acid after deprotection, can also be added, generate salt chemical combination
Thing, such as adds hydrochloric acid, forms the compound of following structural formula:
As preferred technical scheme, compound shown in the formula (III) in above-mentioned steps (1) can use document
" Scalable Synthesis of Strained Cyclooctyne Derivatives " (Synthesis.2014,46,
669-677. the method reported in) is prepared, reaction expression is as follows:
As preferred technical scheme, compound shown in the formula (IV) in above-mentioned steps (2) can use document " Scalable
Synthesis of Strained Cyclooctyne Derivatives " (Synthesis. 2014,46,669-677.)
Middle reported method is prepared, and reaction expression is as follows:
As preferred technical scheme, compound shown in the formula V in above-mentioned steps (3) can use document " Scalable
Synthesis of Strained Cyclooctyne Derivatives " (Synthesis. 2014,46,669-677.)
Middle reported method is prepared, and reaction expression is as follows:
As preferred technical scheme, above-mentioned step (4) includes following sub-step: under the temperature conditions of 0 ~ 25 DEG C,
During compound is dissolved in oxolane shown in formula V, it is added thereto to alkali in batches；Finish, after continuing stirring, then be added thereto to adopt
With oxolane as the Benzenecarbonyl chloride. solution of solvent, after continuing stirring reaction completely, cancellation is reacted, and organic facies is entered by extraction
Row washing, is dried, obtains compound shown in formula (VI).The oxolane that described oxolane newly steams；Preferably add shrend
Go out reaction；During extraction, it is preferred to use ethyl acetate extracts；
As further preferred technical scheme, 1 ~ 2 hour described response time；Adopt when described organic facies is washed
With the sodium hydroxide solution that concentration is 0.5 mol/L；
1mL oxolane adds compound shown in 0.05 ~ 0.1g formula V；
Compound shown in formula V is 1:1.2 with the ratio of the amount of the material of sodium hydride；
Compound shown in formula V is 1:1.2 with the ratio of the amount of the material of Benzenecarbonyl chloride.；
Described employing oxolane as in the Benzenecarbonyl chloride. solution of solvent, the bulking value of Benzenecarbonyl chloride. and oxolane
Ratio is 1.0 ~ 2.0 g/mL；
Described alkali is NaH, and compound shown in formula V is 1:1.2 with the ratio of the amount of the material of NaH.
As preferred technical scheme, described step (5) includes following sub-step :-25oC~15oAt a temperature of C, by formula
(VI), during compound is dissolved in dichloromethane shown in, the bromine solution using dichloromethane as solvent under stirring, is dripped wherein,
Dripping and finish, continue stirring, after question response terminates, cancellation is reacted, and separates organic facies, and described organic facies is washed, and is dried, obtains formula
(VII) compound shown in.Preferably employ sodium sulfite saturated solution cancellation reaction；During washing organic facies, use Asia the most successively
Sodium sulfate saturated solution is washed twice, and washing once, then washes twice with saturated nacl aqueous solution.
As further preferred technical scheme, temperature is 0 DEG C；Response time is 2 ~ 3 hours；
1mL dichloromethane adds compound shown in 0.05 ~ 0.1g formula (VI)；
Compound shown in formula (VI) is 1:1 with the ratio of the amount of the material of bromine；
Under described stirring wherein dropping use dichloromethane as in the bromine solution of solvent, bromine and dichloromethane
Volume ratio is 0.2 ~ 0.4:1.
As preferred technical scheme, described step (6) includes following sub-step: suspended by compound shown in formula (VII)
In alcoholic solvent in, under stirring, be added thereto to potassium tert-butoxide, finish, react at a temperature of 25 ~ 90 DEG C, question response completely after,
Cancellation is reacted, and then extracts, and organic facies is washed, and is dried, obtains compound shown in formula (VIII).The cancellation that preferably adds water is reacted；
Preferably employ dichloromethane to extract, during washing organic facies, it is preferred to use saturated common salt is washed three times.
As further preferred technical scheme, temperature is solvent reflux temperature；Described alcoholic solvent is the alcohol of C1-C4, excellent
Elect the tert-butyl alcohol as；The described response time is 4 ~ 6 hours；
The 1mL tert-butyl alcohol adds compound shown in 0.1 ~ 0.15g formula (VII)；
Compound shown in formula (VII) is 1:2.5 with the ratio of the amount of the material of potassium tert-butoxide；
As preferred technical scheme, described step (7) includes following sub-step: suspended by compound shown in formula (VIII)
In ethanol, 1mL ethanol adds compound shown in 0.1 ~ 0.15g formula (VIII), under stirring, the hydrochloric acid being added thereto to, institute
The concentration stating hydrochloric acid is preferably 6 mol/L, and hydrochloric acid is 1 ~ 2:1 with the volume ratio of ethanol, finishes, anti-at a temperature of 25 ~ 100 DEG C
Should, preferably 100oC, the response time is 4 ~ 6 hours, after question response is complete, is cooled to room temperature, then filters, and solid washs
After, obtain azepine dibenzo cyclooctyne hydrochlorate.Using ethyl acetate to wash during washing solid the most successively twice, ethanol washes one
Secondary, ether is washed once.
Compared with prior art, it is an advantage of the current invention that: the present invention with 5-dibenzosuberenone as initiation material, warp
Cross the reactions such as oximate, Beckmann rearrangement, reduction of amide, protection, addition, debrominate, deprotection and obtain end product azepine hexichol
And cyclooctyne hydrochlorate, total recovery more than 73.6%.Its raw material is simple and easy to get, and convenient post-treatment easily operates, and total recovery is higher.This
Invention has synthesized the azepine dibenzo cyclooctyne compounds of unsubstituted on nitrogen-atoms first, can be to carry on synthetic nitrogen atom
The azepine dibenzo cyclooctyne compounds of different substituents provides new method, is difficult to additive method especially for some
On the nitrogen-atoms of preparation, the azepine dibenzo cyclooctyne compounds of band different substituents, can be former with the product of the present invention
Material, replaces the R base that the H above nitrogen needs.
Accompanying drawing explanation
Fig. 1 is compound shown in Formula V1H NMR schemes；
Fig. 2 is compound shown in Formula VII1H NMR schemes；
Fig. 3 is embodiment 5 gained compound1H NMR schemes；
Fig. 4 is embodiment 5 gained compound13C NMR schemes；
Fig. 5 is the mass spectrum of embodiment 5 gained compound.
Detailed description of the invention
Below in conjunction with accompanying drawing, the invention will be further described.
Embodiment 1
The synthesis of following compound
Compound 5-dibenzosuberenone 40 g shown in formula (II), oxammonium hydrochloride. 67.4 is added in the round-bottomed flask of 1L
G, is then added thereto to dehydrated alcohol 480 mL, pyridine 104 mL, is heated to reflux 15 h；After TLC monitoring reaction completely, cooling
To room temperature, system with 100 mL diluted ethyl acetate, adds 1 M hydrochloric acid 500 mL, stirs half an hour；With ethyl acetate (3 ×
200 mL) extraction, merge organic facies, organic facies saturated aqueous common salt (2 × 150 mL) washs, and organic facies anhydrous sodium sulfate is done
Dry, filter, be concentrated to give above-claimed cpd 41.3 g white solid, yield is 96%.
Embodiment 2
The synthesis of following compound
Addition compound 3 in the round-bottomed flask of 1L, 7-bis-fluoro-5-dibenzosuberenone 48 g, oxammonium hydrochloride. 68 g,
Then it is added thereto to dehydrated alcohol 500 mL, pyridine 104 mL, is heated to reflux 15 h；After TLC monitoring reaction completely, it is cooled to
Room temperature, system with 100 mL diluted ethyl acetate, adds 1 M hydrochloric acid 500 mL, stirs half an hour；With ethyl acetate (3 ×
200 mL) extraction, merge organic facies, organic facies saturated aqueous common salt (2 × 150 mL) washs, and organic facies anhydrous sodium sulfate is done
Dry, filter, be concentrated to give above-claimed cpd 49.1 g white solid, yield is 95%.
Embodiment 3
The synthesis of following compound
Preparation Eaton reagent: 25 g phosphorus pentoxides are dissolved in 200 mL Loprazolams.
In 500 mL round-bottomed flasks, add compound shown in 41.3 g formulas (IIIa), under argon shield, once add
Above-mentioned joined Eaton reagent.Now, system becomes kermesinus at once, then is placed at 100 DEG C stirring reaction half an hour.Will
Reactant liquor is directly poured in 1L mixture of ice and water, separates out white solid, filters, and filter cake washes with water 2 ~ 3 times, and dry under infrared lamp
Dry white powdery solids 41.2 g, i.e. above-claimed cpd, yield 99.8%.
Embodiment 4
The synthesis of following compound
Preparation Eaton reagent: 25 g phosphorus pentoxides are dissolved in 200 mL Loprazolams.
In 500 mL round-bottomed flasks, add compound shown in 49.1 g formulas (IIIb), under argon shield, once add
Above-mentioned joined Eaton reagent.Now, system becomes kermesinus at once, then is placed at 100 DEG C stirring reaction half an hour.Will
Reactant liquor is directly poured in 1L mixture of ice and water, separates out white solid, filters, and filter cake washes with water 2 ~ 3 times, and dry under infrared lamp
Dry white powdery solids 48.6g, i.e. above-claimed cpd, yield 99%.
Embodiment 5
The synthesis of following compound
Compound 20.2 g, lithium aluminium hydride reduction 57.0 g shown in formula (IVa) is added in 500 mL three neck round bottoms；Machinery
Stirring to two material mixings, under argon shield, be slowly added dropwise absolute ether 300 mL wherein, system produces a large amount of gas simultaneously
Body, reactant liquor becomes glassy yellow.Drip and finish, by reactant mixture heating reflux reaction 15 h；After TLC detection reaction completely, by it
It is placed under ice-water bath and is cooled to 0 DEG C, under stirring, be slowly added dropwise water wherein complete to the whole cancellation of lithium aluminium hydride reduction in system.Cross
Filter, filtering residue ethyl acetate washes (3 × 200 mL).From filtrate, separate organic facies, be dried with anhydrous sodium sulfate, filter, filtrate
Concentrating under reduced pressure obtains above-claimed cpd yellow solid 18.3 g, yield 97%.
1H NMR (CDCl3, 300 MHz) d: 4.30 (bs, 1H), 4.60 (s, 2H), 6.39 (d, 1H),
6.48 (d, 1H), 6.57 (d, 1H), 6.66 (t, 1H), 6.89 (t, 1H), 7.00 (d, 1H), 7.18-
7.28 (m, 4H), as shown in Figure 1.
Embodiment 6
The synthesis of following compound
Compound 23.5g, lithium aluminium hydride reduction 57.0 g shown in formula (IVb) is added in 500 mL three neck round bottoms；Machinery
Stirring to two material mixings, under argon shield, be slowly added dropwise absolute ether 310 mL wherein, system produces a large amount of gas simultaneously
Body, reactant liquor becomes glassy yellow.Drip and finish, by reactant mixture heating reflux reaction 15 h；After TLC detection reaction completely, by it
It is placed under ice-water bath and is cooled to 0 DEG C, under stirring, be slowly added dropwise water wherein complete to the whole cancellation of lithium aluminium hydride reduction in system.Cross
Filter, filtering residue ethyl acetate washes (3 × 200 mL).From filtrate, separate organic facies, be dried with anhydrous sodium sulfate, filter, filtrate
Concentrating under reduced pressure obtains above-claimed cpd yellow solid 21.2 g, yield 96%.
Embodiment 7
The synthesis of following compound
Compound 17 g, anhydrous tetrahydro furan 250 mL shown in formula (Va) is added in 500 mL round-bottomed flasks；Put
After stirring is cooled to 0 DEG C under ice-water bath, in solution, it is dividedly in some parts sodium hydride 4.0 g, finishes, stir 20 minutes；To system
Oxolane (10 mL) solution of middle dropping Benzenecarbonyl chloride. (13.8 g).Drip and finish, remove ice-water bath, continue stirring half little
Shi Hou, TLC monitoring reaction is completely.Being poured in appropriate frozen water, extract by ethyl acetate (3 × 100 mL), organic facies is with 0.5
Mol/L sodium hydroxide solution (2 × 100 mL) washs, and organic facies anhydrous sodium sulfate is dried, and decompression steams solvent and obtains Lycoperdon polymorphum Vitt admittedly
Body formula (VI, R1=R2=H) shown in compound.This gray solid is all placed in 500 mL round bottom beakers, adds 250 mL bis-
Chloromethanes, after ice-water bath is cooled to 0 DEG C, drips dichloromethane (12 mL) solution of bromine (4.2 mL) wherein.Drip and finish, continue
After continuous stirring 2 h, TLC detection reaction is completely.It is added thereto to appropriate saturated sodium bisulfite solution, and q. s. methylene chloride, point
Going out organic facies, organic facies is washed by saturated sodium bisulfite solution successively, washing, and saturated common salt is washed, and anhydrous sodium sulfate is dried, decompression
Solvent is evaporated off, obtains above-claimed cpd white solid 34.7 g, two step total recoverys 90%.
1H NMR (DMSO-d6, 300 MHz) d: 4.57 (d, 0.41H), 4.98 (d, 0.53H), 5.54
(d, 0.50H), 5.62-5.80 (m, 0.80H), 5.88 (d, 0.51H), 6.15 (d, 0.50H), 6.41-6.45
(m, 1.00H), 6.75-6.85 (t, 0.57H), 6.97-7.45 (m, 9.86H), 7.52-7.57 (m, 1.50H),
7.67 (d, 0.67H), as shown in Figure 2.
Embodiment 8
The synthesis of following compound
Compound 20 g, anhydrous tetrahydro furan 260 mL shown in formula (Vb) is added in 500 mL round-bottomed flasks；Put
After stirring is cooled to 0 DEG C under ice-water bath, in solution, it is dividedly in some parts sodium hydride 4.0 g, finishes, stir 20 minutes；To system
Oxolane (10 mL) solution of middle dropping Benzenecarbonyl chloride. (13.8 g).Drip and finish, remove ice-water bath, continue stirring half little
Shi Hou, TLC monitoring reaction is completely.Being poured in appropriate frozen water, extract by ethyl acetate (3 × 100 mL), organic facies is with 0.5
Mol/L sodium hydroxide solution (2 × 100 mL) washs, and organic facies anhydrous sodium sulfate is dried, and decompression steams solvent and obtains solid type
(VI, R1=R2=F) shown in compound.This solid is all placed in 500 mL round bottom beakers, adds 250 mL dichloromethane, ice
After water-bath is cooled to 0 DEG C, drip dichloromethane (12 mL) solution of bromine (4.2 mL) wherein.Drip and finish, continue stirring 2 h
Rear TLC detection reaction is completely.It is added thereto to appropriate saturated sodium bisulfite solution, and q. s. methylene chloride, separates organic facies,
Organic facies is washed by saturated sodium bisulfite solution successively, washing, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and removes solvent under reduced pressure,
Obtain above-claimed cpd white solid 37.8 g, two step total recoverys 89%.
Embodiment 9
The synthesis of following structural formula compound
Compound 31.2 g, the tert-butyl alcohol 250 mL shown in formula (VIIa) is added in 500 mL round-bottomed flasks；Under stirring, to
Wherein add potassium tert-butoxide 18.6 g.Finish, by reactant mixture heating reflux reaction 6 h, TLC detection reaction completely.Add
Suitable quantity of water cancellation is reacted, and dichloromethane (3 × 100 mL) extracts, and organic facies saturated common salt is washed 2 times, and anhydrous sodium sulfate is done
Dry, filter, filtrate decompression steams solvent and obtains buff white solid formula (VIII, R1=R2=H) shown in compound.By this buff white solid
All it is placed in 500 mL round-bottomed flasks, adds 120 mL ethanol, be stirred at room temperature down, add 6 M hydrochloric acid 130 mL, heat back
Flow 7 h.After TLC detection reaction completely, removing oil bath, question response liquid is cooled to room temperature, sucking filtration, and filter cake is washed by ethyl acetate successively
2 times, ethanol washes 1 time, and ether is washed 1 time, drains to obtain light yellow powder solid compound as implied above 14.0g, two step total recoverys
88%。
1H NMR (DMSO-d6, 300 MHz) d: 5.19 (s, 2H), 6.67 (s, 1H), 7.03 (t, 1H),
7.14 (t, 1H), 7.36 (t, 1H), 7.44 (t, 2H), 7.60 (d, 2H), 7.80 (d, 1H), such as Fig. 3 institute
Show；
13C NMR (DMSO-d6, 75 MHz) d: 48.3, 90.9, 109.8, 119.3, 120.6, 121.1,
124.0,127.0,128.0,132.1,133.5,142.1, as shown in Figure 4；
HRMS (ESI) Calcd for C15H12N [M]+: 206.0964;Found:206.0955, as shown in Figure 5.
Embodiment 10
The synthesis of following structural formula compound
Compound 36.6 g, the tert-butyl alcohol 280 mL shown in formula (VIIb) is added in 500 mL round-bottomed flasks；Under stirring, to
Wherein add potassium tert-butoxide 18.6 g.Finish, by reactant mixture heating reflux reaction 6 h, TLC detection reaction completely.Add
Suitable quantity of water cancellation is reacted, and dichloromethane (3 × 100 mL) extracts, and organic facies saturated common salt is washed 2 times, and anhydrous sodium sulfate is done
Dry, filter, filtrate decompression steams solvent and obtains solid type (VIII, R1=R2=F) shown in compound.This solid is all placed in 500
In mL round-bottomed flask, add 120 mL ethanol, be stirred at room temperature down, add 6 M hydrochloric acid 130 mL, be heated to reflux 7 h.TLC examines
After measured reaction is complete, removing oil bath, question response liquid is cooled to room temperature, sucking filtration, and filter cake is washed 2 times by ethyl acetate successively, and ethanol washes 1
Secondary, ether is washed 1 time, drains to obtain light yellow powder solid compound as implied above 19.5g, two step total recoverys 86%.
Embodiment 11
The synthesis of following structural formula compound
R is added in 500 mL flasks1=R2The cyclooctyne 20.5g of compound azepine dibenzo shown in the formula (I) of=H, pyridine
25 mL, nitrogen is protected, and adds dichloromethane 150 mL, is cooled to 0oC, dropping Hexadecanoyl chloride 79 mL. dropping is complete to be risen to
Room temperature, continues reaction 5 hours, adds 50 mL dchloromethane, washs (3 × 100 mL) with 1M HCl, then washes, full
And brine It.Organic facies anhydrous sodium sulfate is dried, and filters, removing dichloromethane is concentrated in vacuo, obtains yellow oil,
Above-mentioned off-white color solid 50g, yield 80% is obtained after this grease is purified.
From embodiment 11 it can be seen that the present invention major advantage is that with formula (I) compound for general character intermediate, can
To need to synthesize the azepine dibenzo cyclooctyne compounds of band different substituents on a series of nitrogen-atoms according to click chemistry.
Claims (6)
1. the preparation method of an azepine dibenzo cyclooctyne compounds, it is characterised in that the structural formula of described compound leads to
Formula is as shown in the formula (I):
Wherein:
R in formula (I)1, R2For H, halogen；
And R1, R2For arbitrarily may replace the substituent group of position on phenyl ring, its preparation method comprises the steps:
(1) with 5-dibenzosuberenone as initiation material, through being condensed to yield compound shown in formula (III)；
(2) compound shown in formula (III) obtains compound shown in formula (IV) through Beckmann rearrangement synthesis；
(3) compound shown in formula (IV) obtains compound shown in formula V through reduction synthesis；
(4) compound shown in formula V again on nitrogen protection group synthesis obtain compound shown in formula (VI)；
(5) compound shown in formula (VI) is by obtaining compound shown in formula (VII) with bromine addition synthesis；
(6) compound shown in formula (VII) is then passed through debrominate and prepares compound shown in formula (VIII)；
(7) compound shown in formula (VIII) eventually passes deprotection to prepare compound shown in formula (I), i.e. azepine dibenzo ring pungent
Alkynes；
Its synthetic route is:
Described step (4) includes following sub-step: under the temperature conditions of 0 ~ 25 DEG C, and compound shown in formula V is dissolved in tetrahydrochysene furan
In muttering, it is added thereto to alkali in batches；Finish, after continuing stirring, then be added thereto to the benzene first using oxolane as solvent
Solution of acid chloride, after continuing stirring reaction completely, cancellation is reacted, and organic facies is washed by extraction, is dried, obtains formula (VI) institute
Show compound；
Described step (5) includes following sub-step :-25oC~15oAt a temperature of C, compound shown in formula (VI) is dissolved in dichloromethane
In alkane, under stirring, dropping uses dichloromethane as the bromine solution of solvent wherein, drips and finishes, and continues stirring, and question response terminates
After, cancellation is reacted, and separates organic facies, and described organic facies is washed, and is dried, obtains compound shown in formula (VII)；
Described step (6) includes following sub-step: be suspended in alcoholic solvent by compound shown in formula (VII), under stirring, wherein
Adding potassium tert-butoxide, finish, react at a temperature of 25 ~ 90 DEG C, after question response is complete, cancellation is reacted, and then extracts, by organic facies
Washing, is dried, obtains compound shown in formula (VIII)；
Described step (7) includes following sub-step: be suspended in ethanol by compound shown in formula (VIII), adds in 1mL ethanol
Compound shown in 0.1 ~ 0.15g formula (VIII), under stirring, is added thereto to hydrochloric acid, and the concentration of described hydrochloric acid is 6 mol/L, salt
Acid is 1 ~ 2:1 with the volume ratio of ethanol, finishes, and reacts at a temperature of 25 ~ 100 DEG C, and the response time is 4 ~ 6 hours, and question response is complete
Quan Hou, is cooled to room temperature, then filters, and after solid washing, obtains azepine dibenzo cyclooctyne hydrochlorate.
Preparation method the most according to claim 1, it is characterised in that 1 ~ 2 hour described step (4) response time；To institute
State the sodium hydroxide solution using concentration to be 0.5 mol/L when organic facies is washed；
1mL oxolane adds compound shown in 0.05 ~ 0.1g formula V；
Compound shown in formula V is 1:1.2 with the ratio of the amount of the material of Benzenecarbonyl chloride.；
Described employing oxolane is as in the Benzenecarbonyl chloride. solution of solvent, and Benzenecarbonyl chloride. with the w/v of oxolane is
1.0~2.0 g / mL；
Described alkali is NaH, and compound shown in formula V is 1:1.2 with the ratio of the amount of the material of NaH.
Preparation method the most according to claim 1, it is characterised in that described step (5) temperature is 0 DEG C；Response time is 2
~ 3 hours；1mL dichloromethane adds compound shown in 0.05 ~ 0.1g formula (VI)；
Compound shown in formula (VI) is 1:1 with the ratio of the amount of the material of bromine；
Described employing dichloromethane is as in the bromine solution of solvent, and bromine is 0.2 ~ 0.4:1 with the volume ratio of dichloromethane.
Preparation method the most according to claim 1, it is characterised in that described step (6) temperature is solvent reflux temperature；Institute
State the alcohol that alcoholic solvent is C1-C4；The described response time is 4 ~ 6 hours；
The 1mL tert-butyl alcohol adds compound shown in 0.1 ~ 0.15g formula (VII)；
Compound shown in formula (VII) is 1:2.5 with the ratio of the amount of the material of potassium tert-butoxide.
Preparation method the most according to claim 1, it is characterised in that in described step (7), reacts at a temperature of 100 DEG C.
Preparation method the most according to claim 4, it is characterised in that described alcoholic solvent is the tert-butyl alcohol.
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