CN103172646A - Novel synthetic method for replacing multi-thiophthene with alkyl - Google Patents
Novel synthetic method for replacing multi-thiophthene with alkyl Download PDFInfo
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- 0 *c([s]c1c2[s]c(Br)c1Br)c2Br Chemical compound *c([s]c1c2[s]c(Br)c1Br)c2Br 0.000 description 1
- ATXCLUUASHDQEO-UHFFFAOYSA-N CC1(c([s]cc2Br)c2SC1)Br Chemical compound CC1(c([s]cc2Br)c2SC1)Br ATXCLUUASHDQEO-UHFFFAOYSA-N 0.000 description 1
- XBGVRFWQIOGAPR-UHFFFAOYSA-N Cc([s]cc1)c1[Br]=C Chemical compound Cc([s]cc1)c1[Br]=C XBGVRFWQIOGAPR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a method for replacing multi-thiophthene with beta-dialkyl in a synthesis formula I. The method comprises the following steps of: (f) reacting an intermediate in a formula 10 to obtain an intermediate in a formula 11; (g) reacting the intermediate in the formula 11 to obtain an intermediate in a formula 12; (h) reacting the intermediate in the formula 12 to obtain an intermediate in a formula 13; (i) reacting the intermediate in the formula 13 to obtain an intermediate in a formula 8; (j) reacting the intermediate in the formula 8 to obtain an intermediate in a formula 9; and (k) reacting the intermediate in the formula 9 to obtain a compound in a formula I. The invention further relates to the intermediate in the formula 9. The method disclosed by the invention is low in cost, simple in process, high in yield and low in pollution. The formulas 10, 11, 12, 13, 8 and 9 are shown in the description.
Description
Technical field
The present invention relates to a kind of new synthesis of alkyl replaces and many thiophene; particularly also the above alkyl of four thiophene replaces the also method of many thiophene; method of the present invention from and 2n thiophene bromide; by twice Friedel-Crafts acylations and twice cyclization; the preparation alkyl replaces and the 2n+2 thiophene, and the alkyl that especially alkyl replaces and four thiophene are above replaces and many thiophene.It is that a kind of with low cost, technique is simple, high yield, oligosaprobic synthetic method.
Background technology
Large conjugated organic molecule has special electronics and photoelectronics characteristic, has been extensively studied and has been applied in field effect transistor (FETs), thin film transistor (TFTs), Organic Light Emitting Diode (OLEDs).Develop based on electronic tag (RFID tags), flat-panel display device and the photovoltaic device of organic molecule at present.Pentacene (pentacene) class condensed ring line style compound is exactly the ideal organic semiconductor material of a class, but its main drawback is poorly soluble in organic solvent under room temperature, and very easily oxidized in air, its OFET film preparation need to be adopted vacuum vapour deposition, the complex process of relative wet process film, and the hydrogen transfer reactions on easy generating material molecule in evaporate process, generate impurity, and cause performance to reduce.
Pentacene (pentacene) and four thiophene (tetrathienoacene)
Condensed ring thiophene not only has good electronics property, also has higher environmental stability, for example compound and four thiophene (or four and penthienate, tetrathienoacene).But present semiconducter device based on condensed ring thiophene is also few, and mainly contain the reason of two aspects: 1) condensed ring thiophene is poorly soluble; 2) and the Study of synthesis method of four thiophene above (namely also (2n+2) thiophene, n 〉=1) limited, synthetic difficulty is larger, cost is high, is unfavorable for industry's enlarging production.The researchist of Corning company has reported that recently alkyl replaces the synthetic method of condensed ring (and two to and seven) thiophene; this compounds can significantly solve the solubility problem in common organic solvents; thereby improve the efficient of device preparation, be particularly conducive to the large-scale production of device.The alkyl of its report replaces the also synthetic route following (route one) of four thiophene, referring to J.Org.Chem.2007, and 72,442-451:
Reaction scheme one
Wherein, raw material 1,4-Dithiapentalene tetrabromide 5 is synthetic by following methods, referring to J.Chem.Soc., and Perkin Trans.1,1997,3465.
Synthesizing of raw material 1,4-Dithiapentalene tetrabromide (compound 5)
The characteristics of above reaction scheme one be by and 2n thiophene (wherein n=1) pass through single step reaction, obtain also (2n+2) thiophene, be applicable in a small amount of situation, there are problems in the quick synthetic and fused ring compound more than three thiophene for synthesizing in a large number.For example, 1) n-BuLi is comparatively expensive and dangerous, needs at low temperatures that (78 ℃) use, and can make that to amplify production cost high; 2) corresponding long-chain aldehyde compound (one of reaction raw materials) need to be generated by pure oxidation, the TEMPO (2 that if use cost is minimum, environmental pollution is minimum, 2,6,6 ,-tetramethyl piperidine-1-oxide compound) oxidation, tend to because deliquescent problem, make reaction system very huge, seriously restricted and amplified the efficient of producing; 3) this reaction scheme uses Na in a large number
2Cr
2O
7(being 5-10 equivalent of reaction substrate) can produce and contain in a large number Cr waste water, and environment is worked the mischief.4) amplify yield and be starkly lower than lab scale, especially 6 the reaction from intermediate 5 to intermediate, under the amplification condition, yield only has 10%, and the product that obtains is difficult to purify.Possible reason is: the pairs of anion that n-BuLi (n-Butyl Lithium) reaction of compound 5 and two equivalents (2eq) forms, with the aldehyde solution that adds rapidly (because carbon chain length is poor over 10 alkyl aldehydes solvability) rapid reaction, the monoalkylated product that at first pairs of anion forms with the chain alkyl aldehyde reaction of a part, its solvability is very poor, can separate out in a large number, thereby cause reaction mostly to rest on the monoalkylated product stage.
And by Fu-Ke (Friedel-Crafts) acylation reaction; 2 at thiophene are carried out acidylate (because carbonyl is electron withdrawing group; after thiophene carries out single acidylate; generally all can not directly carry out acidylate for the second time), need to by close again ring realize by and synthetic also (2n+1) thiophene of 2n thiophene, for example synthetic method of the β of Corning company report-two replacement 1,4-Dithiapentalenes; referring to J.Org.Chem.2007; 72,442-451, wherein Hex represents hexyl.
The synthetic method of β-two replacement 1,4-Dithiapentalenes
It is relatively low that the synthetic method of above this β-two replacement 1,4-Dithiapentalenes is considered to combined coefficient, and reactions steps is many.Generally be not used in also synthesizing of the also many thiophene more than three thiophene.
Therefore, seek a kind of cheap, efficient and oligosaprobic Industrialized synthesis method is and the key of many thiophene application.
Summary of the invention
The objective of the invention is to overcome the following problem that exists in prior art: the problem that 1) yield is low, production cost is high; 2) problem of severe reaction conditions in prior art; 3) produce the problem that contains in a large number Cr waste water in prior art; And/or 4) need to prepare the problem of the low chain alkyl aldehyde (one of reaction raw materials) of production efficiency in prior art.
For realizing purpose of the present invention; the invention provides a kind of new from and 2n thiophene synthesis of alkyl replaces and the method for 2n+2 thiophene; method of the present invention from and 2n thiophene beta-2-dibrom compound (synthetic 1,4-Dithiapentalene bromide of n 〉=1) wherein; by twice Fu-Ke (Friedel-Crafts) acylation reaction and twice cyclization; thereby the preparation alkyl is that replace and many thiophene (wherein n 〉=1), especially alkyl replace and four thiophene (wherein n=1).
One aspect of the present invention provides the β of synthesis type I-two alkyl to replace and the method for many thiophene,
Formula I
In formula I and following chemical formula, R is the alkyl of C1-C40, the chain alkyl of preferred C8-C24, and the more preferably chain alkyl of C11-C22, the chain alkyl of further preferred C15-C19, n is the integer more than or equal to 1,
Described method comprises:
F) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 10 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, add aqueous hydrochloric acid and stir, be incubated and stir for some time at 20～25 ℃ after complete, standing, organic phase is washed in phase-splitting, dry, filter, concentrate rear drying, obtain the intermediate of formula 11
Formula 10
Formula 11;
G) add intermediate, salt of wormwood, hexaoxacyclooctadecane-6-6 and second organic solvent of formula 11 in the reactor, make reactor be warming up to 60～65 ℃, be added dropwise to ethyl thioglycolate in reactor within for some time, and continue to be incubated for some time between 60～65 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, obtains the intermediate of formula 12
Formula 12;
H) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 12 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, add aqueous hydrochloric acid and stir, add after dropwising into the first organic solvent and be incubated and stir for some time at 20-25 ℃, obtain the intermediate of formula 13
Formula 13;
I) make intermediate, salt of wormwood and the hexaoxacyclooctadecane-6-6 of the formula 13 in the second organic solvent be placed in reactor, under agitation being warming up to approximately after nitrogen replacement, 60 ℃ of dropping ethyl thioglycolates react, 60-65 ℃ of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue to react fully approaching to raw material reaction, centrifugal, the filter cake that obtains is the intermediate of formula 8
Formula 8;
J) make intermediate, a hydronium(ion) oxidation lithium and the tetrabutylammonium iodide of the formula 8 in the first mixed solvent be placed in reactor, under agitation be warming up to reflux temperature and react, maintenance refluxes, and is complete to raw material reaction, obtains the intermediate of formula 9
Formula 9;
K) make intermediate, glycine and the Red copper oxide of the formula 9 in the 3rd organic solvent be placed in reactor, under agitation heat up, slowly be warming up to 200～260 ℃ and react, reaction is under agitation carried out, till there is no γ-ray emission, obtain the compound of formula I.
Another aspect of the present invention also provides a kind of compound of formula 9,
Formula 9
Wherein, identical with following formula I compound of the definition of R and n.
Method of the present invention is that a kind of with low cost, technique is simple, high yield, oligosaprobic synthetic method, and it can avoid problem in the prior art, the problem includes: yield is low, production cost is high, severe reaction conditions and produce and contain in a large number the such problem of Cr waste water.
Embodiment
The specific embodiment of the present invention below is provided.Those skilled in the art should understand that wherein embodiment is only for illustrative purposes, should not be regarded as limiting by any way the scope of the invention defined by the claims.
For solving the problems of the technologies described above; the invention provides a kind of from and 2n thiophene beta-2-dibrom compound; prepare by twice Friedel-Crafts acylations and twice cyclization the method that β-two alkyl replace also 2n+2 thiophene (wherein n is 〉=1 even number) (as shown in following reaction scheme two), especially β-two alkyl replacements and four thiophene (wherein n=1) (as shown in following reaction scheme three).Method of the present invention is that a kind of with low cost, technique is simple, high yield, oligosaprobic synthetic method.
Reaction scheme two
Reaction scheme three
In a specific embodiment of the present invention; provide a kind of from the synthetic 1,4-Dithiapentalene bromide of 2-bromothiophene, prepared β-two heptadecane bases by twice Friedel-Crafts acylations and twice cyclization and replace the also method (as shown in following reaction scheme four) of four thiophene.
Reaction scheme four
Method of the present invention is that a kind of with low cost, technique is simple, high yield, oligosaprobic synthetic method, and is as shown to reaction scheme four in above reaction scheme two.
Synthesis of alkyl of the present invention replaces and the synthetic route of four thiophene can be by 3, the 4-dibromo thiophene sets out and synthesizes a series of β-two alkyl replacements and many thiophene, wherein also the number of many thiophene is to get final product more than four, each reaction cycle can increase by two thiophthene rings, and the alkyl that this reaction characteristics is also prior art replaces and the synthetic route institute of four thiophene is irrealizable.
Above synthetic route two is synthetic with reference to the literature method of having reported to the synthetic method of the raw material 1,4-Dithiapentalene beta-2-dibrom compound of synthetic route four, and concrete route is as follows:
The synthetic method of raw material 1,4-Dithiapentalene beta-2-dibrom compound
One embodiment of the present of invention provide the β of synthesis type I-two alkyl to replace and the method for many thiophene,
Formula I
In formula I and following chemical formula, R is the alkyl of C1-C40, and preferred R is the chain alkyl of C8-C24, and more preferably R is the chain alkyl of C11-C22, and further preferred R is the chain alkyl of C15-C19, and n is the integer more than or equal to 1,
Described method comprises:
F) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 10 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, add aqueous hydrochloric acid and stir, be incubated and stir for some time at 20～25 ℃ after complete, standing, organic phase is washed in phase-splitting, dry, filter, concentrate rear drying, obtain the intermediate of formula 11
Formula 10
Formula 11;
G) add intermediate, salt of wormwood, hexaoxacyclooctadecane-6-6 and second organic solvent of formula 11 in the reactor, make reactor be warming up to 60～65 ℃, be added dropwise to ethyl thioglycolate in reactor within for some time, and continue to be incubated for some time between 60～65 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, obtains the intermediate of formula 12
Formula 12;
H) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 12 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, add aqueous hydrochloric acid and stir, add after dropwising into the first organic solvent and be incubated and stir for some time at 20-25 ℃, obtain the intermediate of formula 13
Formula 13;
I) make intermediate, salt of wormwood and the hexaoxacyclooctadecane-6-6 of the formula 13 in the second organic solvent be placed in reactor, under agitation being warming up to approximately after nitrogen replacement, 60 ℃ of dropping ethyl thioglycolates react, 60-65 ℃ of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue to react fully approaching to raw material reaction, centrifugal, the filter cake that obtains is the intermediate of formula 8
Formula 8;
J) make intermediate, a hydronium(ion) oxidation lithium and the tetrabutylammonium iodide of the formula 8 in the first mixed solvent be placed in reactor, under agitation be warming up to reflux temperature and react, maintenance refluxes, and is complete to raw material reaction, obtains the intermediate of formula 9
Formula 9;
K) make intermediate, glycine and the Red copper oxide of the formula 9 in the 3rd organic solvent be placed in reactor, under agitation heat up, slowly be warming up to 200～260 ℃ and react, reaction is under agitation carried out, till there is no γ-ray emission, obtain the compound of formula I.
In a preferred embodiment, step f) and/or step h) in alkyl acyl chloride RCOCl obtain by following steps:
Add alkyl fatty acid RCOOH and excessive thionyl chloride in reactor, nitrogen replacement, first be warming up to 35～45 ℃, reaction for some time, then temperature rising reflux 6～8h are until raw material disappears, be cooled to 35～45 ℃, thionyl chloride is removed in decompression, obtains alkyl acyl chloride RCOCl, and wherein the definition of R is with above identical.
In a preferred embodiment, the β of formula I-two alkyl replacements and many thiophene are selected from β-two alkyl replacements, and also four thiophene, β-two alkyl substituted alkyls replace hexa-thiophens, β-two alkyl replacements and eight thiophene, β-two alkyl replacements also ten thiophene, perhaps their both above mixtures.It will be appreciated by those skilled in the art that β according to synthesis type I of the present invention-two alkyl replace and the method for many thiophene, can synthesize that β-two alkyl arbitrarily replace and the many thiophene of even number, be not limited to above listed β-two alkyl and replace and many thiophene.
Replace and the method for many thiophene according to the β of synthesis type I of the present invention-two alkyl, wherein, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
1-40COCl and C
1-40COOH.Preferably, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
8-24COCl and C
8-24COOH, more preferably C
11-23COCl and C
11-23COOH, more preferably C
12-18COCl and C
12-18COOH.Preferably, the R group in alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is saturated.
Replace and the method for many thiophene according to the β of synthesis type I of the present invention-two alkyl, wherein, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
11H
23COCl and C
11H
23COOH, C
12H
25COCl and C
12H
22COOH, C
13H
27COCl and C
13H
27COOH, C
14H
29COCl and C
14H
29COOH, C
15H
31COCl and C
15H
31COOH, C
16H
33COCl and C
16H
33COOH, C
17H
35COCl and C
17H
35COOH, C
18H
37COCl and C
18H
37COOH, C
19H
39COCl and C
19H
39COOH, C
20H
41COCl and C
20H
41COOH, C
21H
43COCl and C
21H
43COOH, C
22H
45COCl and C
22H
45COOH or C
23H
47COCl and C
23H
47COOH.
Preferably, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
18COCl and C
18COOH, especially C
17H
35COCl and C
17H
35COOH.
in a preferred embodiment, step f) and the first organic solvent h) be selected from methylene dichloride (DCM), ethylene dichloride, propylene dichloride, be preferably methylene dichloride (DCM), step g) and the second organic solvent i) be selected from N, dinethylformamide (DMF), N, N-dimethyl methyl ethanamide, be preferably N, dinethylformamide (DMF), step j) the first mixed solvent in is selected from methyl alcohol and tetrahydrofuran compound, ethanol and tetrahydrofuran compound, Virahol and tetrahydrofuran compound, be preferably methyl alcohol and tetrahydrofuran compound, step k) the 3rd organic solvent in is selected from tetraethylene glycol dimethyl ether, the Tetraglycol 99 diethyl ether, be preferably tetraethylene glycol dimethyl ether.
In a preferred embodiment, method of the present invention, wherein in formula I and following chemical formula, R is the alkyl of C17, and n is the integer more than or equal to 1, and the method comprises:
f) add stearic acid in reactor, thionyl chloride 85.0Kg, be warming up to approximately 40～45 ℃, reaction 0.5～1.5h, temperature rising reflux 6-8h again, complete to raw material reaction, be cooled to approximately 40 ℃, remove thionyl chloride under reduced pressure and obtain stearyl chloride, add methylene dichloride again in reactor, make the reactor insulation between 10～15 ℃, the intermediate that will be dissolved in the formula 10 in organic solvent is added dropwise in 1～2h in the reactor that aluminum trichloride (anhydrous) is housed, and continuation insulation 0.5～2h between 10～15 ℃, the solution that obtains is added dropwise in 1～2h in the reactor that the stearyl chloride dichloromethane solution is housed, after question response is complete, add aqueous hydrochloric acid and stir, be incubated and stir for some time at 20～25 ℃ after dropwising, standing, phase-splitting, water is used dichloromethane extraction again, merge organic phase, wash with aqueous hydrochloric acid, wash respectively with saturated sodium bicarbonate aqueous solution and water again, use dried over sodium sulfate, filter, solution can not be concentrated into after solvent dry, obtain the intermediate of formula 11
Formula 10
Formula 11;
G) add intermediate, salt of wormwood, hexaoxacyclooctadecane-6-6 and the dimethyl formamide (DMF) of formula 11 in the reactor, make reactor be warming up to 60～65 ℃, follow-up continuation of insurance temperature about 30-50h between 60～65 ℃ ethyl thioglycolate is added dropwise to reactor in about 0.5～5h in, after question response is complete, temperature of reaction kettle is down to below 10 ℃, obtains the intermediate of formula 12
Formula 12;
h) add stearic acid and thionyl chloride in reactor, be warming up to 35～45 ℃ after nitrogen replacement, reaction 0.5-1.5h, then temperature rising reflux 6-8h are cooled to approximately 40 ℃, remove thionyl chloride under reduced pressure and obtain stearyl chloride, add methylene dichloride in reactor, make the reactor insulation between 10～15 ℃, the intermediate that will be dissolved in the formula 12 in methylene dichloride is added dropwise in 1～2h in the reactor that aluminum trichloride (anhydrous) is housed, and continuation insulation 0.5～1.5h between 10～15 ℃, the solution that obtains is added dropwise in 1～2h in the reactor that the stearyl chloride dichloromethane solution is housed, after question response is complete, temperature of reaction kettle is down to below 10 ℃, add aqueous hydrochloric acid and stir, add methylene dichloride after dropwising, be incubated and stir 0.3-1h at 20-30 ℃, standing, phase-splitting, the washing organic phase, dry, remove by filter siccative, obtain the intermediate of formula 13 after concentrated
Formula 13;
I) make intermediate, salt of wormwood and the hexaoxacyclooctadecane-6-6 of the formula 13 in dimethyl formamide (DMF) be placed in reactor, under agitation being warming up to approximately after nitrogen replacement, 60 ℃ of dropping ethyl thioglycolates react, 60-65 ℃ of insulation for some time, add ethyl thioglycolate and continue to react fully approaching to raw material reaction at dimethyl formamide (DMF), centrifugal, the filter cake that obtains is the intermediate of formula 8
Formula 8;
J) make intermediate, a hydronium(ion) oxidation lithium and the tetrabutylammonium iodide of the formula 8 in methyl alcohol and tetrahydrofuran (THF) mixed solvent be placed in reactor, under agitation be warming up to reflux temperature and react, maintenance refluxes, and is complete to raw material reaction, obtains the intermediate of formula 9
Formula 9;
K) make intermediate, glycine and the Red copper oxide of the formula 9 in tetraethylene glycol dimethyl ether be placed in reactor, under agitation heat up, slowly being warming up to 200～260 ℃ reacts, reaction is under agitation carried out, till there is no γ-ray emission, be cooled to approximately 140 ℃ of hot pressing filters, the filtrate that obtains contains the compound of formula I.
One more preferably in embodiment, step k wherein) further comprise: filtrate is cooled to approximately 15～20 ℃, standing, centrifugal, the filter cake petroleum ether, add toluene to refluxing, the insulation backflow is 0.3-1h approximately, is cooled to gradually 15～20 ℃ again, centrifugal, the filter cake petroleum ether, vacuum-drying obtains the compound crystal of pure formula I.
In another embodiment of the present invention, a kind of compound of formula 9 also is provided, it is the intermediate of preparation formula I compound of the present invention
Formula 9
Wherein, identical with following formula I compound of the definition of R and n.
The specific embodiment of the present invention below is provided.Those skilled in the art should understand that wherein embodiment is only for illustrative purposes, should not be regarded as limiting by any way the scope of the invention defined by the claims.
Embodiment
(I) instrument
Chromatogram: the GC9900 chromatographic instrument that adopts Beijing bonus point analytical instrument company.
Chromatographic condition: instrument numbering: 09-9A-01009; Post type: SE54; Post specification: 30m * 0.32mm * 0.5 μ m; Carrier gas type: N
2Carrier gas flux: 20mL/min; Sample size: 0.4 μ L; Detector: FID; Hydrogen: 30mL/min; Temperature: 280 ℃; Sampler: shunting; Splitting ratio: 60: 1; Temperature: 250 ℃.
Nuclear magnetic resonance analyser: the AV400 nuclear magnetic resonance analyser that adopts Bruker company.
(II) experiment
Embodiment 1
Step 1:
Under nitrogen protection, add Diisopropylamine (51.6Kg, 509.9mol, 1.1eq), anhydrous THF (385.0Kg) in the 1000L reactor, cooling and holding temperature drip n-BuLi (131.4Kg, 463.8mol, 1.05eq) at 0～5 ℃.After dropwising, holding temperature continues to stir half an hour under 0～5 ℃.Under 0～5 ℃, drip THF (20.0Kg) solution of 3 bromo thiophene (starting raw material 1) (75.0Kg, 460.0mol, 1.0eq).After dropwising, holding temperature continues to stir half an hour under 0～5 ℃.Under 0～5 ℃, drip THF (10.0Kg) solution of DMF (35.3Kg, 473.3mol, 1.03eq).Dropwise, holding temperature continues to stir 3 hours under 0～5 ℃.Drip 14% NH under 0～5 ℃
4The Cl aqueous solution (700.0Kg).After dropwising, under 0～5 ℃, stirred 15 minutes, standing 15 minutes, organic phase is temporarily stored in clean tetrafluoroethylene bucket.In water suction reactor, add methyl tertiary butyl ether (150.0Kg), stirred after 15 minutes standing 15 minutes, upper organic phase is got in phase-splitting.Above organic phase is merged, add anhydrous sodium sulphate (85.0Kg), dry a few hours are to moisture＜1%.Filter filter cake methyl tertiary butyl ether washed twice (20Kg * 2), N
2The lower concentrating under reduced pressure desolventizing of protection obtains 3 bromo thiophene-2-formaldehyde (intermediate 2) (93.8Kg, yield 100%).
1HNMR(400MHz，CDCl
3)δ＝7.11(1H，d，J＝5.0)，7.69(1H，dd，J＝1.4，J＝5.0)，9.92(1H，d，J＝1.4)。
Step 2:
Under nitrogen protection, add intermediate 2 (93.0Kg, 460.0mol, 1.0eq) in the 200L reactor, ethyl thioglycolate (55.8Kg, 464.4mol, 1.01eq), DMF (578.3Kg).Temperature control is higher than 25 ℃, N
2Under protection, add K in batches
2CO
3(82.6Kg, 597.7mol, 1.3eq).Be warmed up to 25～30 ℃, the raw material HPLC of stirring reaction to the reaction mixture＜1%.Reaction adds entry (615.0Kg) after finishing, and stirs 15 minutes.Then add methylene dichloride (450.0Kg) to stir 15 minutes, standing 15 minutes, phase-splitting, take off a layer organic phase, water adds methylene dichloride (450.0Kg) to stir again 15 minutes, standing 15 minutes, tells organic phase, merge above organic phase, added anhydrous sodium sulphate (90.0Kg) dry 3 hours.Suction filtration, filter cake washed with dichloromethane (30.0Kg * 2).N
2Under protection, first be warmed up to 35～40 ℃ of decompression rotary evaporations, remove methylene dichloride; be warmed up to 85～90 ℃ of decompression rotary evaporations again and remove DMF, the crude product that obtains is through rapid column chromatography (PE:EA=30); the concentrated product 3 (95.5Kg, 97.9%) that obtains.
1H?NMR(400MHz，CDCl
3)δ＝1.37(3H，t，J＝7.0)，4.34(2H，q，J＝7.0，CH2)，7.24(1H，d，J＝6,55.0，)，7.55(1H，d，J＝5,65.0)，7.97(1H，s)。
Step 3:
Under nitrogen protection, add a hydronium(ion) oxidation lithium (17.8Kg, 662.4mol, 1.47eq), H in the 2000L reactor
2O (440.0Kg) stirs, and makes a hydronium(ion) oxidation lithium water-soluble.Under room temperature, suction intermediate 3 (95.5Kg, 449.8mol, 1.0eq), then suction THF (379.5Kg) in the reactor.Be heated to backflow (approximately 100 ℃), reacted 3 hours.Cool to 35～40 ℃, under nitrogen protection, the decompression rotary evaporation is removed tetrahydrofuran (THF).Add entry (200Kg) in reactor.Control temperature below 20 ℃, add concentrated hydrochloric acid (74.6Kg).Suction filtration, filter cake be with cold water washing 3 times (20Kg), more centrifugally do not obtain product 4 (146Kg, yield 100%) to not going out liquid.
Step 4:
Under nitrogen protection, add in the 2000L reactor intermediate 4 (53.2Kg calculates by 100% yield, only has 30Kg, other be water, 162.8mol, 1.0eq), AcOH (1500.0Kg).Start stirring, reactor temperature is elevated to 50～55 ℃, suction water (150.0Kg), holding temperature drips bromine (39.1Kg, 244.4mol, 1.5eq.) under 50～55 ℃, dropwise follow-up continuation of insurance temperature stirring reaction 1 hour.Be heated to reflux, close exhaust-valve, keep the lower bromine (130.3Kg, 814.4mol, 5.0eq) that drips that refluxes.Dropwise follow-up continuation of insurance temperature and reflux, stirring reaction 3 hours.Sampling monitoring is until the tribromo intermediate is less than 10%.Stir borehole cooling to 70 and ℃ carry out heat filtering.Filter cake water (30.0Kg) washs to filtrate without color, drains, and obtains off-white color solid 5 (52.0Kg, water content is 14%, yield 60.4%) after drying.
Step 5:
Glacial acetic acid (300.0Kg) by header tank accurate weighing of suction in the 500L reactor of drying.Add solid 5 (64.0Kg, 140.4mol, 1.0eq.) in still, add zinc powder (27.0Kg, 415.4mol, 3.0eq).Be warming up to 110 ℃, reacted 1 hour.Utilize HPLC to follow the tracks of reaction, when raw material disappears, stopped reaction.Be cooled to 40-50 ℃ after reacting completely, remove solvent acetic acid under reduced pressure, to substantially not after fluid, be cooled to room temperature, add ethyl acetate (300.0Kg), stirred 30 minutes.Filter, solid is with ethyl acetate (20.0Kg * 2) washing, and merging filtrate in the suction reactor, adds entry (300.0Kg) in reactor, stirred 20 minutes, separatory after standing 20 minutes (if very difficult separatory, can suction filtration after separatory).Tell water, organic phase is stayed in reactor, suction 6.6% aqueous sodium hydroxide washes is washed organic phase (300.0Kg * 2) in the reactor, make water pH＞7, and then in the reactor suction water (200.0Kg) washing once, organic phase was with dry 2 hours of sodium sulfate (30.0Kg).Concentrated organic phase is taken out and is dried to anhydrous, the solvent-free product 10 (31.4Kg, 76.6%) that obtains.
1HNMR(400MHz，CDCl
3)7.32(2H，s)。
Step 6:
Add stearic acid (19.7Kg, 57.6mol, 1.2eq.) in the 200L reactor, suction thionyl chloride (145.0Kg), nitrogen replacement 1 time.First be warming up to 40 ℃, reacted 1 hour, then temperature rising reflux 6-8 hour.Be cooled to 40 ℃, remove thionyl chloride under reduced pressure; After being concentrated into not fluid, suction methylene dichloride (20.0Kg), and then be concentrated into not fluid.To 200L reactor suction methylene dichloride (450.0Kg) in batches, stirred 15 minutes, be pressed in the 1000L reactor, then be cooled to 10～15 ℃, add rapidly aluminum trichloride (anhydrous) (13.3Kg, 99.7mol, 1.73eq.).Raw material 10 is dissolved in DCM (450.0Kg), is added drop-wise in reactor, control 10～15 ℃ of temperature, maintain the temperature at after dropwising and continue between 10～15 ℃ to stir 1 hour, utilize TLC to follow the tracks of reaction.Reaction is added dropwise to 2M hydrochloric acid (330.0Kg) after finishing.Dropwise, continue to stir 0.5 hour.Standing, separatory.Water is used DCM (50.0Kg) extraction again, merges organic phase; Organic phase is washed with 0.6M aqueous hydrochloric acid (300.0Kg * 2); Saturated sodium bicarbonate aqueous solution (300.0Kg) is washed once, then water (300.0Kg) washes once, then adds sodium sulfate (75Kg) dry 2 hours in organic phase.It is dry that loft drier is put in filtration drying agent, filter cake, obtains yellow solid powder-product 11 (33.6Kg, 100%).
Step 7:
Under nitrogen protection, add 11 (36.58Kg, 64.8mol), salt of wormwood (35.83Kg, 259.2mol), hexaoxacyclooctadecane-6-6 (18-Crown-6) (1.83Kg) in the 500L reactor.Suction DMF (170.0Kg) in the reactor.Start and stir and heating, after system is warming up to 60 ℃, drip ethyl thioglycolate (7.79Kg, 64.8mol) in reactor, 60～65 ℃ of insulations utilize TLC to follow the tracks of reaction.Approximately 42 hours rear center bodies of reaction disappear, and reaction solution are cooled to＜10 ℃, and are centrifugal.Filter cake adds water (200.0Kg), stirs 0.5 hour, then emits centrifugal.Filter cake adds the methylene dichloride (180.0Kg) of recovery to be stirred to dissolving fully, then adds aqueous hydrochloric acid (50.0Kg) washing of 0.5M once.Water (100.0Kg) washing once again, added anhydrous sodium sulphate (15.0Kg) dry 2 hours, the filtration drying agent, be concentrated into not fluid, then take out crude product and put into the vacuum drying oven drying, oven dry is to anhydrous, the solvent-free yellow solid product 12 (21.6Kg, 59.0%) that obtains.
Step 8:
Add stearic acid (15.2Kg, 53.5mol, 1.45eq.) in the 200L reactor, suction thionyl chloride (85.0Kg), nitrogen replacement 1 time.First be warming up to 40 ℃, reacted 1 hour, then temperature rising reflux 6-8 hour.Be cooled to 40 ℃, remove thionyl chloride under reduced pressure; After can not being concentrated into liquid, suction methylene dichloride (20.0Kg), and then till can not being concentrated into liquid.Suction methylene dichloride (430.0Kg) in batches in the 200L reactor stirred 15 minutes, was pressed in the 1000L reactor, then was cooled to 10-15 ℃, added rapidly aluminum trichloride (anhydrous) (10.7Kg, 80.2mol, 2.2eq.).Raw material 12 (21.6Kg, 36.9mol, 1.0eq.) is dissolved in DCM (430.0Kg), is added drop-wise in reactor by header tank, control 10～15 ℃ of temperature, dropwise rear maintenance temperature and stirred 1 hour.Reactor temperature is down to below 10 ℃, then adds 2M aqueous hydrochloric acid (300.0Kg) by header tank.Dropwise, add methylene dichloride (200.0Kg), maintain the temperature at 25 ℃ of left and right and stirred 0.5 hour.Standing, separatory.Water is used methylene dichloride (50.0Kg) extraction again, merges organic phase; Organic phase 0.6M aqueous hydrochloric acid (300.0Kg * 2) washed twice; (300.0Kg) washes once with saturated sodium bicarbonate aqueous solution, then water (300.0Kg) is washed once, then added sodium sulfate (60.0Kg) dry 2 hours in organic phase, remove by filter siccative, after can not being concentrated into solvent, the loft drier drying is put in the crude product taking-up, obtain yellow solid powder-product 13 (34.5Kg, 100%)
Step 9:
Add product 13 (34.5Kg, 40.5mol, 1.0eq.), salt of wormwood (22.4Kg, 162.3mol, 4.0eq.) and hexaoxacyclooctadecane-6-6 (18-Crown-6) in the 500L reactor (1.72Kg), nitrogen replacement 1 time.By header tank suction DMF (185.0Kg) in the reactor, nitrogen replacement 1 time.Start and stir and heating, after system is warming up to 60 ℃, drip ethyl thioglycolate (5.35Kg, 44.5mol, 1.1eq.) in reactor, be incubated 60-65 ℃ to react.Reacted stopped reaction 72 hours.Reaction solution is directly emitted carry out centrifugal under 60 ℃, filter cake is with DMF (50.0Kg) making beating, and then centrifugal till do not go out liquid.Filter cake adds water (200.0Kg), stirs 0.5 hour, and then taking-up is carried out centrifugal.Filter cake takes out and to add dehydrated alcohol (80.0Kg) making beating, stirs to disperse, and then pours in whizzer centrifugal till do not go out liquid.Vacuum-drying is carried out in the filter cake taking-up obtained yellow solid product 8 (17.6Kg, 54.2%).Mp.131-132℃，
1H?NMR(400MHz，CDCl3)δ＝4.36(q.4H)，3.15(t，4H)，1.73(m，4H)，1.27(m，34H)，0.87(m，6H)。
Step 10:
Add product 8 (17.6Kg, 20.2mol, 1.0eq.), a hydronium(ion) oxidation lithium (2.54Kg, 60.45mol, 3.0eq.) and tetrabutylammonium iodide (0.18Kg) in the 300L reactor.Suction water (23.0Kg), methyl alcohol (15.8Kg), tetrahydrofuran (THF) (85.0Kg) in the reactor.Start and stir and heating unit, be warming up to backflow, kept back flow reaction 10～12 hours, be cooled to 40 ℃, the concentrating under reduced pressure desolventizing.Add THF (125.0Kg), stirred 1 hour, add 6M hydrochloric acid (15.0Kg), regulate pH to 2, then stirred 1 hour.Be warming up to 40 ℃, concentrating under reduced pressure desolventizing (approximately 80.0Kg).Stop concentrating, add entry (200.0kg) by header tank, stirred 1 hour.Material is put into whizzer centrifugal till do not go out liquid, then water (30Kg) drip washing, more centrifugal till do not go out liquid.Product is taken out put into double cone dryer, temperature control is dried to moisture≤5% at 75-80 ℃, obtains yellow solid powder-product 9 (13.2Kg, 82.5%).
Step 11:
Add product 9 (15.8Kg, 19.3mol, 1.0eq.), glycine (435g in 500L pyroreaction still, 5.8mol, 0.3eq.) and Red copper oxide (553g, 3.8mol, 0.2eq.), then the fresh tetraethylene glycol dimethyl ether of suction (400.0Kg), start stirring.Heating, when temperature rose to 160 ℃, the beginning pyrolysis had γ-ray emission.Slowly be warming up to 220 ℃, keep this temperature until emit without gas, be incubated 1 hour at 220 ℃ again after not producing bubble.After reacting completely, naturally be cooled to 140 ℃ of hot pressing filters.Filtrate cools to 60 ℃ naturally, then changes freezer over to and cools to 15～20 ℃, changes material over to whizzer fully centrifugal, to not having liquid to flow out.Filter cake takes out with sherwood oil (15.0kg) foam washing once, and then pours in whizzer fully centrifugally, and making does not have liquid to flow out in whizzer, then uses sherwood oil (10.0kg) drip washing once.Filter cake is joined in the 300L reactor, add toluene (200.0Kg) by header tank.Start stirring, logical steam is warming up to backflow (110 ℃).Insulation refluxed 30 minutes, naturally cooled to 70 ℃, transferred frequency transformer to reduce stirring velocity, and then logical circulating water cooling to 30～40 ℃ leads to circulating water cooling to 15～20 ℃.Material is emitted from the bottom valve of reactor and is carried out not having liquid to flow out in fully centrifugal extremely centrifugal scheming, filter cake takes out with sherwood oil (20.0kg) foam washing once, and then pour in whizzer fully centrifugal, making does not have liquid to flow out in whizzer, and then with sherwood oil (15.0kg) drip washing once.Product is taken out, put into vacuum drying oven at 40～45 ℃ of temperature dry 12 hours, then sampling detects the fusing point row element analysis of going forward side by side, and the discharging of weighing obtains that white crystal product heptadecane base replaces and four thiophene (10.0Kg, 70.9%).Mp.：111-113℃，
1H?NMR(400MHz，C6D6)δ＝6.53(s，2H)，2.51(t，4H)，1.64(m，4H)，1.27(m，28H)，0.89(t，6H)。
Experimental result:
Following table is the actual production data of 5Kg the finished product FT4 (heptadecane base β-disubstituted and four thiophene) and the comparative result that utilizes prior art to synthesize:
alkyl of the present invention replaces and the synthetic route of four thiophene is on the basis of existing technology, design by different reaction intermediate and reaction scheme, make reaction conditions gentleer, avoided low-temp reaction, decrease solvent load, for the 5Kg the finished product, quantity of solvent is by 42 of prior art, 000L is reduced to 6, 000L, there is no hypertoxic waste liquid in reaction process, especially contain the generation of Cr waste liquid, and final product and intermediate thereof need not to carry out column chromatography and separate to come purifying, avoided the necessary column chromatography of prior art to separate, and the total recovery of the finished product significantly is increased to 8.5% left and right by 0.5% left and right of prior art, significantly improve the batch production alkyl and replaced the also single pass yield of four thiophene, overcome the problem that prior art is brought.
Method of the present invention can be successively take and four thiophene-dibromide, hexa-thiophen-dibromide etc. and many thiophene-dibromide as raw material repeating step 6-step 11 with preparation alkyl β-two replacements and many thiophene, no longer given unnecessary details at this.
The synthetic route of synthesis of alkyl β of the present invention-two replacements and four thiophene can be synthesized a series of alkyl and be replaced and many thiophene, wherein also the number of many thiophene is to get final product more than four, each reaction cycle can increase by two thiophthene rings, and the alkyl that this reaction characteristics is also prior art replaces and the synthetic route institute of four thiophene is irrealizable.
Although various embodiment of the present invention is described in context by embodiment, the present invention is not limited to this.Therefore, it is the restriction of the scope of the invention that above description should be used as, and scope of the present invention is limited by appended claim.It will be appreciated by those skilled in the art that in the situation that do not deviate from spirit of the present invention and can make various changes and change to the present invention, it all will fall within protection scope of the present invention.
Claims (11)
1. the β of a synthesis type I-two alkyl replace the also method of many thiophene,
Formula I
In formula I and following chemical formula, R is the alkyl of C1-C40, the chain alkyl of preferred C8-C24, and the more preferably chain alkyl of C11-C22, the chain alkyl of further preferred C15-C19, n is the integer more than or equal to 1,
Described method comprises:
F) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 10 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, add aqueous hydrochloric acid and stir, be incubated and stir for some time at 20～25 ℃ after complete, standing, organic phase is washed in phase-splitting, dry, filter, concentrate rear drying, obtain the intermediate of formula 11
Formula 10
Formula 11;
G) add intermediate, salt of wormwood, hexaoxacyclooctadecane-6-6 and second organic solvent of formula 11 in the reactor, make reactor be warming up to 60～65 ℃, be added dropwise to ethyl thioglycolate in reactor within for some time, and continue to be incubated for some time between 60～65 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, obtains the intermediate of formula 12
Formula 12;
H) add aluminum trichloride (anhydrous) in the alkyl acyl chloride RCOCl in the first organic solvent in reactor, make the reactor insulation between 10～15 ℃, formula 12 intermediates that will be dissolved in organic solvent are added dropwise in reactor within for some time, and continue to be incubated for some time between 10～15 ℃, after question response is complete, temperature of reaction kettle is down to below 10 ℃, add aqueous hydrochloric acid and stir, add after dropwising into the first organic solvent and be incubated and stir for some time at 20-25 ℃, obtain the intermediate of formula 13
Formula 13;
I) make intermediate, salt of wormwood and the hexaoxacyclooctadecane-6-6 of the formula 13 in the second organic solvent be placed in reactor, under agitation being warming up to approximately after nitrogen replacement, 60 ℃ of dropping ethyl thioglycolates react, 60-65 ℃ of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue to react fully approaching to raw material reaction, centrifugal, the filter cake that obtains is the intermediate of formula 8
Formula 8;
J) make intermediate, a hydronium(ion) oxidation lithium and the tetrabutylammonium iodide of the formula 8 in the first mixed solvent be placed in reactor, under agitation be warming up to reflux temperature and react, maintenance refluxes, and is complete to raw material reaction, obtains the intermediate of formula 9
Formula 9;
K) make intermediate, glycine and the Red copper oxide of the formula 9 in the 3rd organic solvent be placed in reactor, under agitation heat up, slowly be warming up to 200～260 ℃ and react, reaction is under agitation carried out, till there is no γ-ray emission, obtain the compound of formula I.
2. method according to claim 1, wherein, step f) and/or step h) in described alkyl acyl chloride RCOCl obtain by following steps:
Add alkyl fatty acid RCOOH and excessive thionyl chloride in reactor, nitrogen replacement, first be warming up to 35～45 ℃, reaction for some time, then temperature rising reflux 6～8h are until raw material disappears, be cooled to 35～45 ℃, thionyl chloride is removed in decompression, obtains described alkyl acyl chloride RCOCl, and wherein the definition of R is identical with claim 1.
3. method according to claim 1, wherein, the β of described formula I-two alkyl replacements and many thiophene are selected from β-two alkyl replacements, and also four thiophene, β-two alkyl substituted alkyls replace hexa-thiophens, β-two alkyl replacements and eight thiophene, β-two alkyl replacements also ten thiophene, perhaps their both above mixtures.
4. according to claim 2～3 described methods of any one, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
1-40COCl and C
1-40COOH.
5. according to claim 2～3 described methods of any one, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
8-24COCl and C
8-24COOH, preferred C
11-23COCl and C
11-23COOH, more preferably C
12-18COCl and C
12-18COOH.
6. method according to claim 4, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
11H
23COCl and C
11H
23COOH, C
12H
25COCl and C
12H
22COOH, C
13H
27COCl and C
13H
27COOH, C
14H
29COCl and C
14H
29COOH, C
15H
31COCl and C
15H
31COOH, C
16H
33COCl and C
16H
33COOH, C
17H
35COCl and C
17H
35COOH, C
18H
37COCl and C
18H
37COOH, C
19H
39COCl and C
19H
39COOH, C
20H
41COCl and C
20H
41COOH, C
21H
43COCl and C
21H
43COOH, C
22H
45COCl and C
22H
45COOH or C
23H
47COCl and C
23H
47COOH.
7. method according to claim 6, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH are independently selected from C
18COCl and C
18COOH, especially C
17H
35COCl and C
17H
35COOH.
8. according to claim 1～3 described methods, wherein, step f) and described the first organic solvent h) be selected from methylene dichloride (DCM), ethylene dichloride, propylene dichloride, be preferably methylene dichloride (DCM), step g) and described the second organic solvent i) be selected from N, dinethylformamide (DMF), N, N-dimethyl methyl ethanamide, be preferably N, dinethylformamide (DMF), step j) described the first mixed solvent in is selected from methyl alcohol and tetrahydrofuran compound, ethanol and tetrahydrofuran compound, Virahol and tetrahydrofuran compound, be preferably methyl alcohol and tetrahydrofuran compound, step k) described the 3rd organic solvent in is selected from tetraethylene glycol dimethyl ether, the Tetraglycol 99 diethyl ether, be preferably tetraethylene glycol dimethyl ether.
9. according to claim 1～3 described methods, wherein in formula I and following chemical formula, R is the alkyl of C17, n is the integer more than or equal to 1
f) add stearic acid in reactor, thionyl chloride 85.0Kg, be warming up to approximately 40～45 ℃, reaction 0.5～1.5h, temperature rising reflux 6-8h again, complete to raw material reaction, be cooled to approximately 40 ℃, remove thionyl chloride under reduced pressure and obtain stearyl chloride, add methylene dichloride again in reactor, make the reactor insulation between 10～15 ℃, the intermediate that will be dissolved in the formula 10 in organic solvent is added dropwise in 1～2h in the reactor that aluminum trichloride (anhydrous) is housed, and continuation insulation 0.5～2h between 10～15 ℃, the solution that obtains is added dropwise in 1～2h in the reactor that the stearyl chloride dichloromethane solution is housed, after question response is complete, add aqueous hydrochloric acid and stir, be incubated and stir for some time at 20～25 ℃ after dropwising, standing, phase-splitting, water is used dichloromethane extraction again, merge organic phase, wash with aqueous hydrochloric acid, wash respectively with saturated sodium bicarbonate aqueous solution and water again, use dried over sodium sulfate, filter, solution can not be concentrated into after solvent dry, obtain the intermediate of formula 11
Formula 10
Formula 11;
G) add intermediate, salt of wormwood, hexaoxacyclooctadecane-6-6 and the dimethyl formamide (DMF) of formula 11 in the reactor, make reactor be warming up to 60～65 ℃, follow-up continuation of insurance temperature about 30-50h between 60～65 ℃ ethyl thioglycolate is added dropwise to reactor in about 0.5～5h in, after question response is complete, temperature of reaction kettle is down to below 10 ℃, obtains the intermediate of formula 12
Formula 12;
h) add stearic acid and thionyl chloride in reactor, be warming up to 35～45 ℃ after nitrogen replacement, reaction 0.5-1.5h, then temperature rising reflux 6-8h are cooled to approximately 40 ℃, remove thionyl chloride under reduced pressure and obtain stearyl chloride, add methylene dichloride in reactor, make the reactor insulation between 10～15 ℃, the intermediate that will be dissolved in the formula 12 in methylene dichloride is added dropwise in 1～2h in the reactor that aluminum trichloride (anhydrous) is housed, and continuation insulation 0.5～1.5h between 10～15 ℃, the solution that obtains is added dropwise in 1～2h in the reactor that the stearyl chloride dichloromethane solution is housed, after question response is complete, temperature of reaction kettle is down to below 10 ℃, add aqueous hydrochloric acid and stir, add methylene dichloride after dropwising, be incubated and stir 0.3-1h at 20-30 ℃, standing, phase-splitting, the washing organic phase, dry, remove by filter siccative, obtain the intermediate of formula 13 after concentrated
Formula 13;
I) make intermediate, salt of wormwood and the hexaoxacyclooctadecane-6-6 of the formula 13 in dimethyl formamide (DMF) be placed in reactor, under agitation being warming up to approximately after nitrogen replacement, 60 ℃ of dropping ethyl thioglycolates react, 60-65 ℃ of insulation for some time, add ethyl thioglycolate and continue to react fully approaching to raw material reaction at dimethyl formamide (DMF), centrifugal, the filter cake that obtains is the intermediate of formula 8
Formula 8;
J) make intermediate, a hydronium(ion) oxidation lithium and the tetrabutylammonium iodide of the formula 8 in methyl alcohol and tetrahydrofuran (THF) mixed solvent be placed in reactor, under agitation be warming up to reflux temperature and react, maintenance refluxes, and is complete to raw material reaction, obtains the intermediate of formula 9
Formula 9;
K) make intermediate, glycine and the Red copper oxide of the formula 9 in tetraethylene glycol dimethyl ether be placed in reactor, under agitation heat up, slowly being warming up to 200～260 ℃ reacts, reaction is under agitation carried out, till there is no γ-ray emission, be cooled to approximately 140 ℃ of hot pressing filters, the filtrate that obtains contains the compound of formula I.
10. method according to claim 9, step k wherein) further comprise: filtrate is cooled to approximately 15～20 ℃, standing, centrifugal, the filter cake petroleum ether, add toluene to refluxing, the insulation backflow is 0.3-1h approximately, is cooled to gradually 15～20 ℃ again, centrifugal, the filter cake petroleum ether, vacuum-drying obtains the compound crystal of pure formula I.
11. the compound of a formula 9,
Formula 9
Wherein, R is identical with definition and the claim 1 of n.
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