CN103172646B - A kind of new alkyl replaces and the synthetic method of many thiophene - Google Patents
A kind of new alkyl replaces and the synthetic method of many thiophene Download PDFInfo
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- CN103172646B CN103172646B CN201110436338.8A CN201110436338A CN103172646B CN 103172646 B CN103172646 B CN 103172646B CN 201110436338 A CN201110436338 A CN 201110436338A CN 103172646 B CN103172646 B CN 103172646B
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Abstract
β-bis-the alkyl that the invention provides a kind of synthesis type I replaces and the method for many thiophene, comprising: intermediate f) intermediate reaction of formula 10 being obtained formula 11; G) intermediate reaction of formula 11 is obtained the intermediate of formula 12; H) intermediate reaction of formula 12 obtains the intermediate of formula 13; I) intermediate reaction of formula 13 is made to obtain the intermediate of formula 8; J) make the intermediate of formula 8, be obtained by reacting the intermediate of formula 9; K) intermediate reaction of formula 9 is made to obtain the compound of formula I.The invention still further relates to the intermediate of formula 9.Method of the present invention is that one is with low cost, technique simple, high yield, oligosaprobic synthetic method.
formula 10? formula 11? formula 12? formula 13
Description
Technical field
The present invention relates to a kind of new synthesis of alkyl to replace and many thiophene; particularly and four thiophene more than alkyl replace and the method for many thiophene; method of the present invention from and 2n thiophene bromide; by twice Friedel-Crafts acylations and twice cyclization; prepare alkyl replace and 2n+2 thiophene, especially alkyl replace and four thiophene more than alkyl replace and many thiophene.It is that one is with low cost, technique 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).The current electronic tag (RFIDtags) based on organic molecule, flat-panel display device and photovoltaic device are developed.Pentacene (pentacene) class condensed ring linear 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 it is very easily oxidized in atmosphere, its OFET film preparation needs to adopt vacuum vapour deposition, the complex process of relative wet process film, and the hydrogen transfer reactions in evaporate process on easy generating material molecule, generate impurity, and cause performance to reduce.
Condensed ring thiophene not only has good electronics property, also has higher environmental stability, such as compound four thiophene (or four and penthienate, tetrathienoacene).But the semiconducter device at present based on condensed ring thiophene is also few, mainly contains the reason of two aspects: 1) condensed ring thiophene is poorly soluble; 2) and the more than four thiophene Study of synthesis method of (namely also (2n+2) thiophene, n >=1) is limited, synthesis difficulty is comparatively large, and cost is high, is unfavorable for industry's enlarging production.The researchist of Corning company is recently reported the synthetic method that alkyl replaces condensed ring (and two to and seven) thiophene; this compounds can significantly solve the solubility problem in common organic solvents; thus efficiency prepared by raising device, be particularly conducive to the large-scale production of device.The alkyl of its report replaces and the synthetic route of four thiophene following (route one), see J.Org.Chem.2007, and 72,442-451:
Reaction scheme one
Wherein, raw material 1,4-Dithiapentalene tetrabromide 5 is synthesized by following methods, see J.Chem.Soc., PerkinTrans.1, and 1997,3465.
The synthesis of raw material 1,4-Dithiapentalene tetrabromide (compound 5)
The feature of above reaction scheme one be by and 2n thiophene (wherein n=1) passes through single step reaction, obtain also (2n+2) thiophene, be applicable in a small amount in situation, Fast back-projection algorithm more than three thiophene fused ring compound, then problems are existed for a large amount of synthesis.Such as, 1) n-BuLi costly and dangerous, needs (-78 DEG C) at low temperatures to use, can make to amplify production cost and remain high; 2) corresponding long-chain aldehyde compound (one of reaction raw materials) needs to be oxidized by alcohol to generate, the TEMPO (2 that if use cost is minimum, environmental pollution is minimum, 2,6,6 ,-tetramethyl piperidine-1-oxide compounds) oxidation, often because deliquescent problem, make reaction system very huge, seriously constrain the efficiency of amplifying and producing; 3) this reaction scheme uses Na in a large number
2cr
2o
7(5-10 the equivalent for reaction substrate), can produce a large amount of wastewater with chromium, work the mischief to environment.4) amplify yield and be starkly lower than lab scale, especially from intermediate 5 to the reaction of intermediate 6, under amplification condition, yield only has 10%, and the product obtained is difficult to purify.Possible reason is: the n-BuLi (n-Butyl Lithium) of compound 5 and two equivalents (2eq) reacts the pairs of anion formed, with the aldehyde solution added rapidly (because the alkyl aldehydes solvability of carbon chain length more than 10 is poor) rapid reaction, the monoalkylated product that first pairs of anion is formed with the chain alkyl aldehyde reaction of a part, its solvability is very poor, can separate out in a large number, thus 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 directly can not carry out second time acidylate), need by close ring again to realize by and 2n thiophene synthesis also (2n+1) thiophene, the such as synthetic method of β-bis-replacement 1,4-Dithiapentalene of Corning company report; see J.Org.Chem.2007; 72,442-451, wherein Hex represents hexyl.
The synthetic method of β-bis-replacement 1,4-Dithiapentalene
It is relatively low that the synthetic method of this β above-bis-replacement 1,4-Dithiapentalene is considered to combined coefficient, and reactions steps is many.Generally be not used in and three thiophene more than and the synthesis of many thiophene.
Therefore, finding a kind of cheap, efficient and oligosaprobic Industrialized synthesis method is and the key of many thiophene application.
Summary of the invention
The object of the invention is to overcome the following problem existed in prior art: the problem that 1) yield is low, production cost is high; 2) problem of severe reaction conditions in prior art; 3) problem of a large amount of wastewater with chromium is produced in prior art; And/or 4) need the problem preparing the low chain alkyl aldehyde (one of reaction raw materials) of production efficiency in prior art.
For realizing object of the present invention; the invention provides a kind of newly from and 2n thiophene synthesis alkyl replace and the method for 2n+2 thiophene; method of the present invention from and 2n thiophene beta-2-dibrom compound (wherein n >=1) synthesis 1,4-Dithiapentalene bromide; by twice Fu-Ke (Friedel-Crafts) acylation reaction and twice cyclization; thus prepare alkyl replace and many thiophene (wherein n >=1), especially alkyl replace and four thiophene (wherein n=1).
β-bis-alkyl that one aspect of the present invention provides synthesis type I replaces and the method for many thiophene,
In formula I and following chemical formula, R is the chain alkyl of the alkyl of C1-C40, preferred C8-C24, more preferably the chain alkyl of C11-C22, further preferably the chain alkyl of C15-C19, n be more than or equal to 1 integer,
Described method comprises:
F) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 10 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, add aqueous hydrochloric acid and stir, after be incubated at 20 ~ 25 DEG C and stir for some time, leave standstill, phase-splitting, washs organic phase, dry, filter, dry after concentrated, obtain the intermediate of formula 11
G) in reactor, add the intermediate of formula 11, salt of wormwood, hexaoxacyclooctadecane-6-6 and the second organic solvent, reactor is made to be warming up to 60 ~ 65 DEG C, ethyl thioglycolate is added dropwise in reactor within for some time, and continue to be incubated for some time between 60 ~ 65 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, obtains the intermediate of formula 12
H) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 12 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, add aqueous hydrochloric acid and stir, add after dropwising and be incubated into the first organic solvent at 20-25 DEG C and stir for some time, obtain the intermediate of formula 13
I) intermediate of formula 13 in a second organic solvent, salt of wormwood and hexaoxacyclooctadecane-6-6 is made to be placed in reactor, under agitation be warming up to about 60 DEG C of dropping ethyl thioglycolates after nitrogen replacement to react, 60-65 DEG C of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue reaction to raw material reaction close to completely, centrifugal, the filter cake obtained is the intermediate of formula 8
J) make the intermediate of the formula 8 in the first mixed solvent, a hydronium(ion) Lithium Oxide 98min and tetrabutylammonium iodide be placed in reactor, be under agitation warming up to reflux temperature and react, keep backflow, complete to raw material reaction, obtain the intermediate of formula 9
K) intermediate of the formula 9 in the 3rd organic solvent, glycine and Red copper oxide is made to be placed in reactor, under agitation heat up, be slowly warming up to 200 ~ 260 DEG C and react, reaction is under agitation carried out, producing to there is no gas, obtain the compound of formula I.
Another aspect of the present invention additionally provides a kind of compound of formula 9,
Wherein, the definition of R and n and identical with above formula I.
Method of the present invention be a kind of with low cost, technique simple, high yield, oligosaprobic synthetic method, it can avoid problem in the prior art, the problem includes: yield is low, production cost is high, severe reaction conditions and produce the such problem of a large amount of wastewater with chromium.
Embodiment
The following provide the specific embodiment of the present invention.Those skilled in the art should understand that wherein embodiment is only for illustrative purposes, should not be regarded as limiting the scope of the invention defined by the claims by any way.
For solving the problems of the technologies described above; the invention provides a kind of from and 2n thiophene beta-2-dibrom compound; prepare that β-bis-alkyl replaces by twice Friedel-Crafts acylations and twice cyclization and 2n+2 thiophene (wherein n be >=1 even number) (shown by following reaction scheme two), especially β-bis-alkyl replaces and the method for four thiophene (wherein n=1) (shown by following reaction scheme three).Method of the present invention is that one is with low cost, technique 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 2-bromothiophene synthesis 1,4-Dithiapentalene bromide, prepare β-bis-heptadecane base by twice Friedel-Crafts acylations and twice cyclization and replace and the method (shown by following reaction scheme four) of four thiophene.
Reaction scheme four
Method of the present invention is that one is with low cost, technique simple, high yield, oligosaprobic synthetic method, shown by above reaction scheme two to reaction scheme four.
Synthesis of alkyl of the present invention replaces and the synthetic route of four thiophene can by 3,4-dibromo thiophene sets out and synthesizes a series of β-bis-alkyl replacements and many thiophene, wherein and the number of many thiophene is more than four, each reaction cycle can increase by two thiophthene rings, and the synthetic route institute that the alkyl that this reaction characteristics is also prior art replaces also four thiophene is irrealizable.
The synthetic method of the raw material 1,4-Dithiapentalene beta-2-dibrom compound of above synthetic route two to synthetic route four is with reference to the literature method synthesis reported, and concrete route is as follows:
The synthetic method of raw material 1,4-Dithiapentalene beta-2-dibrom compound
β-bis-the alkyl that An embodiment provides synthesis type I replaces and the method for many thiophene,
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 preferably R is the chain alkyl of C15-C19, n be more than or equal to 1 integer,
Described method comprises:
F) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 10 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, add aqueous hydrochloric acid and stir, after be incubated at 20 ~ 25 DEG C and stir for some time, leave standstill, phase-splitting, washs organic phase, dry, filter, dry after concentrated, obtain the intermediate of formula 11
G) in reactor, add the intermediate of formula 11, salt of wormwood, hexaoxacyclooctadecane-6-6 and the second organic solvent, reactor is made to be warming up to 60 ~ 65 DEG C, ethyl thioglycolate is added dropwise in reactor within for some time, and continue to be incubated for some time between 60 ~ 65 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, obtains the intermediate of formula 12
H) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 12 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, add aqueous hydrochloric acid and stir, add after dropwising and be incubated into the first organic solvent at 20-25 DEG C and stir for some time, obtain the intermediate of formula 13
I) intermediate of formula 13 in a second organic solvent, salt of wormwood and hexaoxacyclooctadecane-6-6 is made to be placed in reactor, under agitation be warming up to about 60 DEG C of dropping ethyl thioglycolates after nitrogen replacement to react, 60-65 DEG C of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue reaction to raw material reaction close to completely, centrifugal, the filter cake obtained is the intermediate of formula 8
J) make the intermediate of the formula 8 in the first mixed solvent, a hydronium(ion) Lithium Oxide 98min and tetrabutylammonium iodide be placed in reactor, be under agitation warming up to reflux temperature and react, keep backflow, complete to raw material reaction, obtain the intermediate of formula 9
K) intermediate of the formula 9 in the 3rd organic solvent, glycine and Red copper oxide is made to be placed in reactor, under agitation heat up, be slowly warming up to 200 ~ 260 DEG C and react, reaction is under agitation carried out, producing to there is no gas, obtain the compound of formula I.
In a preferred embodiment, step f) and/or step h) in alkyl acyl chloride RCOCl obtained by following steps:
Alkyl fatty acid RCOOH and excessive thionyl chloride is added in reactor, nitrogen replacement, first be warming up to 35 ~ 45 DEG C, reaction for some time, then temperature rising reflux 6 ~ 8h, until raw material disappears, be cooled to 35 ~ 45 DEG C, thionyl chloride is removed in decompression, and obtain alkyl acyl chloride RCOCl, wherein the definition of R is with identical above.
In a preferred embodiment, the β of formula I-bis-alkyl replaces and many thiophene are selected from that β-bis-alkyl replaces and four thiophene, β-bis-alkyl substituted alkyl replaces hexa-thiophen, β-bis-alkyl replaces and eight thiophene, β-bis-alkyl replaces and ten thiophene, or mixture above both them.It will be appreciated by those skilled in the art that the β-bis-alkyl according to synthesis type I of the present invention replaces and the method for many thiophene, the also many thiophene of even number that arbitrary β-bis-alkyl replaces can be synthesized, be not limited to above listed β-bis-alkyl and replace and many thiophene.
β-bis-alkyl according to synthesis type I of the present invention replaces and the method for many thiophene, and wherein, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is independently selected from CH
3cOCl and CH
3cOOH, C
2h
5cOCl and C
2h
5cOOH, C
3h
7cOCl and C
3h
7cOOH, C
4h
9cOCl and C
4h
9cOOH, C
5h
11cOCl and C
5h
11cOOH, C
6h
13cOCl and C
6h
13cOOH, C
7h
15cOCl and C
7h
15cOOH, C
8h
17cOCl and C
8h
17cOOH, C
9h
19cOCl and C
9h
19cOOH, C
10h
21cOCl and C
10h
21cOOH, 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, C
23h
47cOCl and C
23h
47cOOH, C
24h
49cOCl and C
24h
49cOOH, C
25h
51cOCl and C
25h
51cOOH, C
26h
53cOCl and C
26h
53cOOH, C
27h
55cOCl and C
27h
55cOOH, C
28h
57cOCl and C
28h
57cOOH, C
29h
59cOCl and C
29h
59cOOH, C
30h
61cOCl and C
30h
61cOOH, C
31h
63cOCl and C
31h
63cOOH, C
32h
65cOCl and C
32h
65cOOH, C
33h
67cOCl and C
33h
67cOOH, C
34h
69cOCl and C
34h
69cOOH, C
35h
71cOCl and C
35h
71cOOH, C
36h
73cOCl and C
36h
73cOOH, C
37h
75cOCl and C
37h
75cOOH, C
38h
77cOCl and C
38h
77cOOH, C
39h
79cOCl and C
39h
79cOOH or C
40h
81cOCl and C
40h
81cOOH.
Preferably, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is independently selected from C
8h
17cOCl and C
8h
17cOOH, C
9h
19cOCl and C
9h
19cOOH, C
10h
21cOCl and C
10h
21cOOH, 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, C
23h
47cOCl and C
23h
47cOOH or C
24h
49cOCl and C
24h
49cOOH,
Be more preferably 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,
More preferably 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 or C
18h
37cOCl and C
18h
37cOOH.
Preferably, the R group in alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is saturated.
β-bis-alkyl according to synthesis type I of the present invention replaces and the method for many thiophene, and wherein, alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is 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 is independently selected from C
18cOCl and C
18cOOH, especially C
17h
35cOCl and C
17h
35cOOH.
In a preferred embodiment, step f) and h) in the first organic solvent be selected from methylene dichloride (DCM), ethylene dichloride, propylene dichloride, be preferably methylene dichloride (DCM), step g) and i) in the second organic solvent be selected from N, dinethylformamide (DMF), N, N-dimethyl methyl ethanamide, be preferably N, dinethylformamide (DMF), step j) in the first mixed solvent be selected from methyl alcohol and tetrahydrofuran compound, ethanol and tetrahydrofuran compound, Virahol and tetrahydrofuran compound, be preferably methyl alcohol and tetrahydrofuran compound, step k) in the 3rd organic solvent be selected from tetraethylene glycol dimethyl ether, 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, n be more than or equal to 1 integer, the method comprises:
F) in reactor, stearic acid is added, thionyl chloride 85.0Kg, be warming up to about 40 ~ 45 DEG C, reaction 0.5 ~ 1.5h, temperature rising reflux 6-8h again, complete to raw material reaction, be cooled to about 40 DEG C, remove thionyl chloride under reduced pressure and obtain stearyl chloride, methylene dichloride is added again in reactor, reactor is incubated between 10 ~ 15 DEG C, being added dropwise in 1 ~ 2h by the intermediate of the formula 10 be dissolved in organic solvent is equipped with in the reactor of aluminum trichloride (anhydrous), and continue insulation 0.5 ~ 2h between 10 ~ 15 DEG C, the solution obtained is added dropwise in 1 ~ 2h in the reactor that stearyl chloride dichloromethane solution is housed, after question response is complete, add aqueous hydrochloric acid and stir, be incubated at 20 ~ 25 DEG C and stir for some time after dropwising, leave standstill, phase-splitting, aqueous phase uses dichloromethane extraction again, merge organic phase, wash with aqueous hydrochloric acid, wash respectively with saturated sodium bicarbonate aqueous solution and water again, by dried over sodium sulfate, filter, solution is dry after can not being concentrated into solvent, obtain the intermediate of formula 11
G) in reactor, add the intermediate of formula 11, salt of wormwood, hexaoxacyclooctadecane-6-6 and dimethyl formamide (DMF), reactor is made to be warming up to 60 ~ 65 DEG C, ethyl thioglycolate is added dropwise in about 0.5 ~ 5h follow-up continuation of insurance temperature about 30-50h between 60 ~ 65 DEG C in reactor, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, obtains the intermediate of formula 12
H) in reactor, add stearic acid and thionyl chloride, be warming up to 35 ~ 45 DEG C after nitrogen replacement, reaction 0.5-1.5h, then temperature rising reflux 6-8h, be cooled to about 40 DEG C, remove thionyl chloride under reduced pressure and obtain stearyl chloride, methylene dichloride is added in reactor, reactor is incubated between 10 ~ 15 DEG C, being added dropwise in 1 ~ 2h by the intermediate of the formula 12 be dissolved in methylene dichloride is equipped with in the reactor of aluminum trichloride (anhydrous), and continue insulation 0.5 ~ 1.5h between 10 ~ 15 DEG C, the solution obtained is added dropwise in 1 ~ 2h in the reactor that stearyl chloride dichloromethane solution is housed, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, add aqueous hydrochloric acid and stir, methylene dichloride is added after dropwising, be incubated at 20-30 DEG C and stir 0.3-1h, leave standstill, phase-splitting, washing organic phase, dry, cross and filter siccative, the intermediate of formula 13 is obtained after concentrated
I) intermediate of the formula 13 in dimethyl formamide (DMF), salt of wormwood and hexaoxacyclooctadecane-6-6 is made to be placed in reactor, under agitation be warming up to about 60 DEG C of dropping ethyl thioglycolates after nitrogen replacement to react, 60-65 DEG C of insulation for some time, add ethyl thioglycolate and continue reaction to raw material reaction close to complete at dimethyl formamide (DMF), centrifugal, the filter cake obtained is the intermediate of formula 8
J) intermediate of the formula 8 in methyl alcohol and tetrahydrofuran (THF) mixed solvent, a hydronium(ion) Lithium Oxide 98min and tetrabutylammonium iodide is made to be placed in reactor, under agitation be warming up to reflux temperature to react, keep backflow, complete to raw material reaction, obtain the intermediate of formula 9
K) intermediate of the formula 9 in tetraethylene glycol dimethyl ether, glycine and Red copper oxide is made to be placed in reactor, under agitation heat up, slowly be warming up to 200 ~ 260 DEG C to react, reaction is under agitation carried out, producing to there is no gas, be cooled to about 140 DEG C of hot pressing filters, the filtrate obtained is containing the compound of formula I.
In one more preferably embodiment, wherein step k) comprise further: filtrate is cooled to about 15 ~ 20 DEG C, leaves standstill, centrifugal, filter cake petroleum ether, add toluene again to backflow, be incubated the about 0.3-1h that refluxes, be cooled to 15 ~ 20 DEG C gradually, centrifugal, filter cake petroleum ether, vacuum-drying, obtains the compound crystal of pure formula I.
In another embodiment of the present invention, additionally provide a kind of compound of formula 9, it is the intermediate preparing formula I of the present invention
Wherein, the definition of R and n and identical with above formula I.
The following provide the specific embodiment of the present invention.Those skilled in the art should understand that wherein embodiment is only for illustrative purposes, should not be regarded as limiting the scope of the invention defined by the claims by any way.
Embodiment
(I) instrument
Chromatogram: the GC9900 chromatographic instrument adopting Beijing bonus point analytical instrument company.
Chromatographic condition: instrument is numbered: 09-9A-01009; Post type: SE54; Post specification: 30m × 0.32mm × 0.5 μm; Carrier gas type: N
2; Carrier gas flux: 20mL/min; Sample size: 0.4 μ L; Detector: FID; Hydrogen: 30mL/min; Temperature: 280 DEG C; Sampler: shunting; Splitting ratio: 60:1; Temperature: 250 DEG C.
Nuclear magnetic resonance analyser: the AV400 nuclear magnetic resonance analyser adopting Bruker company.
(II) test
Embodiment 1
Step 1:
(wherein LDA is lithium diisopropyl amido)
Under nitrogen protection, in 1000L reactor, add Diisopropylamine (51.6Kg, 509.9mol; 1.1eq), anhydrous THF (385.0Kg), cooling holding temperature, at 0 ~ 5 DEG C, drip n-BuLi (131.4Kg; 463.8mol, 1.05eq).After dropwising, holding temperature continues to stir half an hour at 0 ~ 5 DEG C.At 0 ~ 5 DEG C, 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 at 0 ~ 5 DEG C.At 0 ~ 5 DEG C, drip THF (10.0Kg) solution of DMF (35.3Kg, 473.3mol, 1.03eq).Dropwise, holding temperature, at 0 ~ 5 DEG C, continues stirring 3 hours.The NH of 14% is dripped at 0 ~ 5 DEG C
4the Cl aqueous solution (700.0Kg).After dropwising, at 0 ~ 5 DEG C, stir 15 minutes, leave standstill 15 minutes, organic phase is temporarily stored in clean tetrafluoroethylene bucket.In aqueous phase suction reactor, add methyl tertiary butyl ether (150.0Kg), stir after 15 minutes and leave standstill 15 minutes, phase-splitting, gets upper organic phase.Above organic phase merged, add anhydrous sodium sulphate (85.0Kg), dry a few hours are to moisture <1%.Filter, filter cake methyl tertiary butyl ether washes twice (20Kg × 2), N
2the lower concentrating under reduced pressure of protection, except desolventizing, 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, in 200L reactor, add intermediate 2 (93.0Kg, 460.0mol, 1.0eq), ethyl thioglycolate (55.8Kg, 464.4mol, 1.01eq), DMF (578.3Kg).Temperature control not higher than 25 DEG C, N
2under protection, add K in batches
2cO
3(82.6Kg, 597.7mol, 1.3eq).Be warmed up to 25 ~ 30 DEG C, stirring reaction is to the raw material HPLC<1% in reaction mixture.After reaction terminates, add water (615.0Kg), stir 15 minutes.Then add methylene dichloride (450.0Kg) and stir 15 minutes, leave standstill 15 minutes, phase-splitting, take off a layer organic phase, aqueous phase adds methylene dichloride (450.0Kg) again and stirs 15 minutes, leaves standstill 15 minutes, separates organic phase, merge above organic phase, add anhydrous sodium sulphate (90.0Kg) dry 3 hours.Suction filtration, filter cake is with washed with dichloromethane (30.0Kg × 2).N
2under protection; first be warmed up to 35 ~ 40 DEG C of decompression rotary evaporations; removing methylene dichloride; be warmed up to 85 ~ 90 DEG C of decompression rotary evaporation removing N again; dinethylformamide; the crude product obtained, through rapid column chromatography (PE:EA=30), concentrates and obtains product 3 (95.5Kg, 97.9%).
1HNMR(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, in 2000L reactor, add a hydronium(ion) Lithium Oxide 98min (17.8Kg, 662.4mol, 1.47eq), H
2o (440.0Kg), stirs, makes a hydronium(ion) Lithium Oxide 98min water-soluble.Under room temperature, suction intermediate 3 (95.5Kg, 449.8mol, 1.0eq) in reactor, then suction THF (379.5Kg).Be heated to backflow (about 100 DEG C), react 3 hours.Cool to 35 ~ 40 DEG C, the rotary evaporation that reduces pressure under nitrogen protection removing tetrahydrofuran (THF).Water (200Kg) is added in reactor.Control temperature less than 20 DEG C, adds concentrated hydrochloric acid (74.6Kg).Suction filtration, filter cake cold water washing 3 times (20Kg), more centrifugally obtain product 4 (146Kg, yield 100%) to not going out liquid.
Step 4:
Under nitrogen protection, add in 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 DEG C, suction water (150.0Kg), holding temperature drips bromine (39.1Kg, 244.4mol, 1.5eq.) at 50 ~ 55 DEG C, dropwises follow-up continuation of insurance temperature stirring reaction 1 hour.Be heated to backflow, close exhaust-valve, under maintaining backflow, drip bromine (130.3Kg, 814.4mol, 5.0eq).Dropwise the backflow of follow-up continuation of insurance temperature, stirring reaction 3 hours.Sampling monitoring, until tribromo intermediate is less than 10%.Stir borehole cooling to 70 DEG C and carry out heat filtering.Filter cake use water (30.0Kg) washing without color to filtrate, is drained, is obtained off-white color solid 5 (52.0Kg, water content is 14%, yield 60.4%) after drying.
Step 5:
By the Glacial acetic acid (300.0Kg) of header tank to suction precise in the 500L reactor of drying.In still, add solid 5 (64.0Kg, 140.4mol, 1.0eq.), add zinc powder (27.0Kg, 415.4mol, 3.0eq).Be warming up to 110 DEG C, react 1 hour.HPLC is utilized to follow the tracks of reaction, when raw material disappears, stopped reaction.Be cooled to 40-50 DEG C 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), stir 30 minutes.Filter, solid with ethyl acetate (20.0Kg × 2) washs, merging filtrate, in suction reactor, in reactor, add water (300.0Kg), stir 20 minutes, leave standstill separatory after 20 minutes (if be difficult to separatory, can after suction filtration separatory).Separate aqueous phase, organic phase is stayed in reactor, suction 6.6% aqueous sodium hydroxide solution washing organic phase (300.0Kg × 2) in reactor, make aqueous phase pH > 7, and then to suction water (200.0Kg) washing in reactor once, dry 2 hours of organic phase with sodium sulfate (30.0Kg).Concentrated organic phase, takes out to be dried to and anhydrous, solvent-freely obtains product 10 (31.4Kg, 76.6%).
1HNMR(400MHz,CDCl
3)7.32(2H,s)。
Step 6:
Stearic acid (19.7Kg, 57.6mol, 1.2eq.) is added, suction thionyl chloride (145.0Kg), nitrogen replacement 1 time in 200L reactor.First be warming up to 40 DEG C, react 1 hour, then temperature rising reflux 6-8 hour.Be cooled to 40 DEG C, remove thionyl chloride under reduced pressure; When being concentrated into not after fluid, suction methylene dichloride (20.0Kg), and then be concentrated into not fluid.To 200L reactor suction methylene dichloride (450.0Kg) in batches, stir 15 minutes, in press-in 1000L reactor, be then cooled to 10 ~ 15 DEG C, 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 temperature 10 ~ 15 DEG C, maintain the temperature at after dropwising between 10 ~ 15 DEG C and continue stirring 1 hour, utilize TLC to follow the tracks of reaction.After reaction terminates, be added dropwise to 2M hydrochloric acid (330.0Kg).Dropwise, continue stirring 0.5 hour.Leave standstill, separatory.Aqueous phase uses DCM (50.0Kg) to extract again, merges organic phase; Organic phase 0.6M aqueous hydrochloric acid (300.0Kg × 2) washs; Saturated sodium bicarbonate aqueous solution (300.0Kg) is washed once, then uses water (300.0Kg) to wash once, in organic phase, then adds sodium sulfate (75Kg) dry 2 hours.Filtration drying agent, it is dry that loft drier put into by filter cake, obtains yellow solid powder-product 11 (33.6Kg, 100%).
Step 7:
Under nitrogen protection, in 500L reactor, add 11 (36.58Kg, 64.8mol), salt of wormwood (35.83Kg, 259.2mol), hexaoxacyclooctadecane-6-6 (18-Crown-6) (1.83Kg).Suction DMF (170.0Kg) in reactor.Start and stir and heating, after system is warming up to 60 DEG C, in reactor, drip ethyl thioglycolate (7.79Kg, 64.8mol), 60 ~ 65 DEG C of insulations, utilize TLC to follow the tracks of reaction.About reaction 42 hours rear center bodies disappear, and reaction solution is cooled to <10 DEG C, centrifugal.Filter cake adds water (200.0Kg), stirs 0.5 hour, then releases centrifugal.The methylene dichloride (180.0Kg) that filter cake adds recovery is stirred to and dissolves completely, then adds aqueous hydrochloric acid (50.0Kg) washing of 0.5M once.Water (100.0Kg) is used to wash once again, add anhydrous sodium sulphate (15.0Kg) dry 2 hours, filtration drying agent, be concentrated into not fluid, then take out crude product and put into vacuum drying oven drying, dry and obtain yellow solid product 12 (21.6Kg, 59.0%) to anhydrous, solvent-free.
Step 8:
Stearic acid (15.2Kg, 53.5mol, 1.45eq.) is added, suction thionyl chloride (85.0Kg), nitrogen replacement 1 time in 200L reactor.First be warming up to 40 DEG C, react 1 hour, then temperature rising reflux 6-8 hour.Be cooled to 40 DEG C, 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 200L reactor, stirs 15 minutes, in press-in 1000L reactor, is then cooled to 10-15 DEG C, adds 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 temperature 10 ~ 15 DEG C, dropwise rear maintenance temperature and stir 1 hour.Reactor temperature is down to less than 10 DEG C, then adds 2M aqueous hydrochloric acid (300.0Kg) by header tank.Dropwise, add methylene dichloride (200.0Kg), maintain the temperature at about 25 DEG C and stir 0.5 hour.Leave standstill, separatory.Aqueous phase uses methylene dichloride (50.0Kg) to extract again, merges organic phase; Organic phase 0.6M aqueous hydrochloric acid (300.0Kg × 2) washes twice; Wash once with saturated sodium bicarbonate aqueous solution (300.0Kg), then water (300.0Kg) is used to wash once, then in organic phase, sodium sulfate (60.0Kg) is added dry 2 hours, cross and filter siccative, after can not being concentrated into solvent, crude product is taken out and put into loft drier drying, obtain yellow solid powder-product 13 (34.5Kg, 100%)
Step 9:
Product 13 (34.5Kg is added in 500L reactor, 40.5mol, l.0eq.), salt of wormwood (22.4Kg, 162.3mol, 4.0eq.) with hexaoxacyclooctadecane-6-6 (18-Crown-6) (1.72Kg), nitrogen replacement 1 time.By header tank to suction DMF (185.0Kg) in reactor, nitrogen replacement 1 time.Start and stir and heating, after system is warming up to 60 DEG C, in reactor, drip ethyl thioglycolate (5.35Kg, 44.5mol, 1.1eq.), be incubated 60-65 DEG C to react.React 72 hours, stopped reaction.Reaction solution is directly released centrifugal to carry out at 60 DEG C, filter cake DMF (50.0Kg) making beating, and then centrifugal to not going 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 adds dehydrated alcohol (80.0Kg) making beating, stirs to disperse, and then pours in whizzer centrifugal to not going out liquid.Vacuum-drying is carried out in filter cake taking-up and obtains yellow solid product 8 (17.6Kg, 54.2%).Mp.131-132℃，
1HNMR(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:
Product 8 (17.6Kg, 20.2mol, 1.0eq.), a hydronium(ion) Lithium Oxide 98min (2.54Kg, 60.45mol, 3.0eq.) and tetrabutylammonium iodide (0.18Kg) is added in 300L reactor.Suction water (23.0Kg), methyl alcohol (15.8Kg), tetrahydrofuran (THF) (85.0Kg) in reactor.Start stirring and heating unit, be warming up to backflow, keep back flow reaction 10 ~ 12 hours, be cooled to 40 DEG C, concentrating under reduced pressure is except desolventizing.Add THF (125.0Kg), stir 1 hour, add 6M hydrochloric acid (15.0Kg), regulate pH to 2, then stir 1 hour.Be warming up to 40 DEG C, concentrating under reduced pressure is except desolventizing (about 80.0Kg).Stop concentrated, add water (200.0kg) by header tank, stir 1 hour.Material is put into whizzer centrifugal to not going out liquid, then use water (30Kg) drip washing, more centrifugal to not going out liquid.Taken out by product and put into double cone dryer, temperature control is dried to moisture≤5% at 75-80 DEG C, obtains yellow solid powder-product 9 (13.2Kg, 82.5%).
Step 11:
Product 9 (15.8Kg is added in 500L pyroreaction still, 19.3mol, 1.0eq.), glycine (435g, 5.8mol, 0.3eq.) with Red copper oxide (553g, 3.8mol, 0.2eq.), then the fresh tetraethylene glycol dimethyl ether of suction (400.0Kg), starts stirring.Heating, when temperature rises to 160 DEG C, starts pyrolysis, has gas to produce.Slowly be warming up to 220 DEG C, keep this temperature until release without gas, again 220 DEG C of insulations 1 hour after not producing bubble.After reacting completely, Temperature fall to 140 DEG C hot pressing filter.Filtrate Temperature fall, to 60 DEG C, then proceeding to freezer and cools to 15 ~ 20 DEG C, material is proceeded to whizzer fully centrifugal, flowing out to not having liquid.Filter cake takes out uses sherwood oil (15.0kg) foam washing once, and then pours in whizzer fully centrifugal, makes do not have liquid to flow out in whizzer, then uses sherwood oil (10.0kg) drip washing once.Filter cake is joined in 300L reactor, add toluene (200.0Kg) by header tank.Start stirring, logical steam is warming up to backflow (110 DEG C).Insulation backflow 30 minutes, Temperature fall, to 70 DEG C, adjusts frequency transformer to reduce stirring velocity, and logical circulating water cooling is to 30 ~ 40 DEG C, and then logical circulating water cooling is to 15 ~ 20 DEG C.Material is released from the bottom valve of reactor and is carried out fully centrifugally to centrifugal scheming, not having liquid to flow out, filter cake takes out uses sherwood oil (20.0kg) foam washing once, and then pour in whizzer fully centrifugal, make in whizzer, do not have liquid to flow out, and then with sherwood oil (15.0kg) drip washing once.Product is taken out, put into vacuum drying oven at temperature 40 ~ 45 DEG C dry 12 hours, then sampling detects fusing point and to go forward side by side row element analysis, discharging of weighing, obtain also four thiophene (10.0Kg, 70.9%) that white crystal product heptadecane base replaces.Mp.:111-113℃，
1HNMR(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 be 5Kg the finished product FT4 (heptadecane base β-disubstituted and four thiophene) actual production data with utilize prior art to carry out the comparative result synthesized:
Alkyl of the present invention replaces and the synthetic route of four thiophene is on the basis of existing technology, by the design of different reaction intermediates and reaction scheme, make reaction conditions gentleer, avoid low-temp reaction, considerably reduce solvent load, for 5Kg the finished product, quantity of solvent is by 42 of prior art, 000L is reduced to 6, 000L, hypertoxic waste liquid is not had in reaction process, especially containing the generation of Cr waste liquid, and final product and intermediate thereof carry out purifying without the need to carrying out pillar layer separation, avoid the pillar layer separation that prior art is necessary, and the total recovery of the finished product is significantly increased to about 8.5% by about 0.5% of prior art, significantly improve batch production alkyl to replace and the single pass yield of four thiophene, overcome the problem that prior art is brought.
Method of the present invention can successively with and four thiophene-dibromide, hexa-thiophen-dibromide etc. many thiophene-dibromide for raw material repeating step 6-step 11 is to prepare alkyl β-bis-replacement and many thiophene, no longer repeated at this.
The synthetic route of synthesis of alkyl β of the present invention-bis-replacement four thiophene can be synthesized a series of alkyl and be replaced and many thiophene, wherein and the number of many thiophene is more than four, each reaction cycle can increase by two thiophthene rings, and the synthetic route institute that the alkyl that this reaction characteristics is also prior art replaces also four thiophene is irrealizable.
Although various embodiment of the present invention is described within a 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 and can make various change and change to the present invention when not deviating from spirit of the present invention, it all will fall within protection scope of the present invention.
Claims (12)
1. β-bis-alkyl of synthesis type I replaces and a method for many thiophene,
In formula I and following chemical formula, R is the chain alkyl of C8-C24, and n is 1,
Described method comprises:
F) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 10 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, add aqueous hydrochloric acid and stir, after be incubated at 20 ~ 25 DEG C and stir for some time, leave standstill, phase-splitting, washs organic phase, dry, filter, dry after concentrated, obtain the intermediate of formula 11
G) in reactor, add the intermediate of formula 11, salt of wormwood, hexaoxacyclooctadecane-6-6 and the second organic solvent, reactor is made to be warming up to 60 ~ 65 DEG C, ethyl thioglycolate is added dropwise in reactor within for some time, and continue to be incubated for some time between 60 ~ 65 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, obtains the intermediate of formula 12
H) in the alkyl acyl chloride RCOCl in the first organic solvent in a kettle., aluminum trichloride (anhydrous) is added, reactor is incubated between 10 ~ 15 DEG C, formula 12 intermediate be dissolved in organic solvent is added dropwise in reactor within for some time, and continue to be incubated for some time between 10 ~ 15 DEG C, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, add aqueous hydrochloric acid and stir, add after dropwising and be incubated into the first organic solvent at 20-25 DEG C and stir for some time, obtain the intermediate of formula 13
I) intermediate of formula 13 in a second organic solvent, salt of wormwood and hexaoxacyclooctadecane-6-6 is made to be placed in reactor, under agitation be warming up to 60 DEG C of dropping ethyl thioglycolates after nitrogen replacement to react, 60-65 DEG C of insulation for some time, add ethyl thioglycolate and the second organic solvent and continue reaction to raw material reaction close to completely, centrifugal, the filter cake obtained is the intermediate of formula 8
J) make the intermediate of the formula 8 in the first mixed solvent, a hydronium(ion) Lithium Oxide 98min and tetrabutylammonium iodide be placed in reactor, be under agitation warming up to reflux temperature and react, keep backflow, complete to raw material reaction, obtain the intermediate of formula 9
K) intermediate of the formula 9 in the 3rd organic solvent, glycine and Red copper oxide is made to be placed in reactor, under agitation heat up, be slowly warming up to 200 ~ 260 DEG C and react, reaction is under agitation carried out, producing to there is no gas, obtain the compound of formula I;
Wherein, described first organic solvent is selected from methylene dichloride or ethylene dichloride or propylene dichloride; Described second organic solvent is selected from DMF or N, N-dimethyl methyl ethanamide; Described 3rd organic solvent is selected from tetraethylene glycol dimethyl ether or Tetraglycol 99 diethyl ether; Described first mixed solvent is selected from methyl alcohol and tetrahydrofuran compound, ethanol and tetrahydrofuran compound or Virahol and tetrahydrofuran compound.
2. method according to claim 1, is characterized in that, R is the chain alkyl of C11-C22.
3. method according to claim 2, is characterized in that, R is the chain alkyl of C15-C19.
4. method according to claim 1, wherein, step f) and/or step h) in described alkyl acyl chloride RCOCl obtained by following steps:
Alkyl fatty acid RCOOH and excessive thionyl chloride is added in reactor, nitrogen replacement, first be warming up to 35 ~ 45 DEG C, reaction for some time, then temperature rising reflux 6 ~ 8h, until raw material disappears, be cooled to 35 ~ 45 DEG C, thionyl chloride is removed in decompression, and obtain described alkyl acyl chloride RCOCl, wherein the definition of R is identical with claim 1.
5. the method according to claim 1 or 4, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is independently selected from C
8h
17cOCl and C
8h
17cOOH, C
9h
19cOCl and C
9h
19cOOH, C
10h
21cOCl and C
10h
21cOOH, 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, C
23h
47cOCl and C
23h
47cOOH or C
24h
49cOCl and C
24h
49cOOH.
6. method according to claim 5, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is 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 is independently selected from 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 or C
18h
37cOCl and C
18h
37cOOH.
8. method according to claim 1, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is independently selected from C
18cOCl and C
18cOOH.
9. method according to claim 1, wherein, described alkyl acyl chloride RCOCl and alkyl fatty acid RCOOH is independently selected from C
17h
35cOCl and C
17h
35cOOH.
10. method according to any one of claim 1 to 4, wherein, described first organic solvent for the second organic solvent described in methylene dichloride be DMF, described first mixed solvent is methyl alcohol and tetrahydrofuran compound, and described 3rd organic solvent is tetraethylene glycol dimethyl ether.
11. methods according to any one of claim 1 to 4, wherein in formula I and following chemical formula, R is the alkyl of C17, and n is 1
F) in reactor, stearic acid is added, thionyl chloride 85.0Kg, be warming up to 40 ~ 45 DEG C, reaction 0.5 ~ 1.5h, temperature rising reflux 6-8h again, complete to raw material reaction, be cooled to 40 DEG C, remove thionyl chloride under reduced pressure and obtain stearyl chloride, methylene dichloride is added again in reactor, reactor is incubated between 10 ~ 15 DEG C, being added dropwise in 1 ~ 2h by the intermediate of the formula 10 be dissolved in organic solvent is equipped with in the reactor of aluminum trichloride (anhydrous), and continue insulation 0.5 ~ 2h between 10 ~ 15 DEG C, the solution obtained is added dropwise in 1 ~ 2h in the reactor that stearyl chloride dichloromethane solution is housed, after question response is complete, add aqueous hydrochloric acid and stir, be incubated at 20 ~ 25 DEG C and stir for some time after dropwising, leave standstill, phase-splitting, aqueous phase uses dichloromethane extraction again, merge organic phase, wash with aqueous hydrochloric acid, wash respectively with saturated sodium bicarbonate aqueous solution and water again, by dried over sodium sulfate, filter, solution is dry after can not being concentrated into solvent, obtain the intermediate of formula 11
G) in reactor, add the intermediate of formula 11, salt of wormwood, hexaoxacyclooctadecane-6-6 and dimethyl formamide, reactor is made to be warming up to 60 ~ 65 DEG C, ethyl thioglycolate is added dropwise in 0.5 ~ 5h follow-up continuation of insurance temperature 30-50h between 60 ~ 65 DEG C in reactor, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, obtains the intermediate of formula 12
H) in reactor, add stearic acid and thionyl chloride, be warming up to 35 ~ 45 DEG C after nitrogen replacement, reaction 0.5-1.5h, then temperature rising reflux 6-8h, be cooled to 40 DEG C, remove thionyl chloride under reduced pressure and obtain stearyl chloride, methylene dichloride is added in reactor, reactor is incubated between 10 ~ 15 DEG C, being added dropwise in 1 ~ 2h by the intermediate of the formula 12 be dissolved in methylene dichloride is equipped with in the reactor of aluminum trichloride (anhydrous), and continue insulation 0.5 ~ 1.5h between 10 ~ 15 DEG C, the solution obtained is added dropwise in 1 ~ 2h in the reactor that stearyl chloride dichloromethane solution is housed, after question response is complete, temperature of reaction kettle is down to less than 10 DEG C, add aqueous hydrochloric acid and stir, methylene dichloride is added after dropwising, be incubated at 20-30 DEG C and stir 0.3-1h, leave standstill, phase-splitting, washing organic phase, dry, cross and filter siccative, the intermediate of formula 13 is obtained after concentrated
I) intermediate of the formula 13 in dimethyl formamide, salt of wormwood and hexaoxacyclooctadecane-6-6 is made to be placed in reactor, under agitation be warming up to 60 DEG C of dropping ethyl thioglycolates after nitrogen replacement to react, 60-65 DEG C of insulation for some time, add ethyl thioglycolate and continue reaction to raw material reaction close to complete at dimethyl formamide, centrifugal, the filter cake obtained is the intermediate of formula 8
J) intermediate of the formula 8 in methyl alcohol and tetrahydrofuran (THF) mixed solvent, a hydronium(ion) Lithium Oxide 98min and tetrabutylammonium iodide is made to be placed in reactor, under agitation be warming up to reflux temperature to react, keep backflow, complete to raw material reaction, obtain the intermediate of formula 9
K) intermediate of the formula 9 in tetraethylene glycol dimethyl ether, glycine and Red copper oxide is made to be placed in reactor, under agitation heat up, slowly be warming up to 200 ~ 260 DEG C to react, reaction is under agitation carried out, producing to there is no gas, be cooled to 140 DEG C of hot pressing filters, the filtrate obtained is containing the compound of formula I.
12. methods according to claim 11, wherein step k) comprise further: filtrate is cooled to 15 ~ 20 DEG C, leaves standstill, centrifugal, filter cake petroleum ether, add toluene again to backflow, insulation backflow 0.3-1h, is cooled to 15 ~ 20 DEG C gradually, centrifugal, filter cake petroleum ether, vacuum-drying, obtains the compound crystal of pure formula I.
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| CN101111497A (en) * | 2004-09-14 | 2008-01-23 | 康宁股份有限公司 | Fused thiophenes, methods for making fused thiophenes, and uses thereof |
| CN101348491A (en) * | 2008-09-11 | 2009-01-21 | 中国科学院化学研究所 | Phenyl ethylene end capped tetrathiophen derivative, preparation and use thereof |
| WO2011146308A1 (en) * | 2010-05-18 | 2011-11-24 | Corning Incorporated | Methods of making fused thiophenes |
| CN102477045A (en) * | 2010-11-30 | 2012-05-30 | 中国科学院上海有机化学研究所 | Thiophene quinoid compound, preparation method, intermediate and application thereof |
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| CN101111497A (en) * | 2004-09-14 | 2008-01-23 | 康宁股份有限公司 | Fused thiophenes, methods for making fused thiophenes, and uses thereof |
| CN101348491A (en) * | 2008-09-11 | 2009-01-21 | 中国科学院化学研究所 | Phenyl ethylene end capped tetrathiophen derivative, preparation and use thereof |
| WO2011146308A1 (en) * | 2010-05-18 | 2011-11-24 | Corning Incorporated | Methods of making fused thiophenes |
| CN102477045A (en) * | 2010-11-30 | 2012-05-30 | 中国科学院上海有机化学研究所 | Thiophene quinoid compound, preparation method, intermediate and application thereof |
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