CN108503500A - A kind of method of the bromo- 1- iodine dihalo objects of one pot process 2- - Google Patents
A kind of method of the bromo- 1- iodine dihalo objects of one pot process 2- Download PDFInfo
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- CN108503500A CN108503500A CN201810133912.4A CN201810133912A CN108503500A CN 108503500 A CN108503500 A CN 108503500A CN 201810133912 A CN201810133912 A CN 201810133912A CN 108503500 A CN108503500 A CN 108503500A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The invention discloses the synthetic methods of 2 bromine shown in a kind of formula (IV), 1 iodine dihalo compound：N hydroxy benzo triazoles shown in tert-butyl hydroperoxide, formula (III) shown in olefin(e) compound shown in formula (I) and propiodal, formula (II) are mixed in organic solvent, in room temperature at 50 DEG C, the reaction was complete obtains reaction solution A；Acetyl bromide is added into gained reaction solution A, the reaction was complete at room temperature, and gained reaction solution B is post-treated to obtain 2 bromine, the 1 iodine dihalo compound.Method safety environmental protection of the present invention does not generate exhaust gas, more conducively its application in medicine synthesizes；Reaction condition is mild, and substrate adaptability is good, and a variety of substituent groups can realize 1 iodine dihalo object of corresponding 2 bromine.
Description
(1) technical field
Present invention relates particularly to a kind of methods with the bromo- 1- iodine dihalo objects of one pot process 2-.
(2) background technology
Dihalo object some natural products and drug molecule it is artificial synthesized in often crucial intermediate, while one
Halides are also highly useful synthon in organic synthesis a bit, so developing novel dihalide reaction either for section
It learns research or actual production is all of great significance.But up to the present, it is reported about the synthetic method of such compound
It is very few.Most common method is exactly directly to carry out halogenation to carbon-carbon double bond using halogen simple substance, although this method is simple,
This method is not easy to operate and easily causes environmental pollution, therefore greatly limits the large-scale application of this method.
(3) invention content
The object of the present invention is to provide a kind of new methods of dihalo object, with olefin(e) compound, propiodal, tertiary butyl mistake
Hydrogen oxide and N- hydroxy benzo triazoles are raw material, are directly added into acetyl bromine reaction without post-processing, in a mild condition may be used
To realize the synthesis of the bromo- 1- iodine dihalo objects of a variety of 2-.
In order to achieve the above objectives, the technical solution adopted by the present invention is as follows：
The synthetic method of the bromo- 1- iodine dihalo objects of 2- shown in a kind of formula (IV), it is characterised in that：The synthetic method
Specifically prepared in accordance with the following steps：
(1) by tert-butyl hydroperoxide, formula shown in substituted olefine compound shown in formula (I) and propiodal, formula (II)
(III) N- hydroxy benzo triazoles shown in are mixed in organic solvent, and in room temperature at 50 DEG C, the reaction was complete obtains reaction solution
A；Olefin(e) compound shown in the formula (I) and N- hydroxyls shown in tert-butyl hydroperoxide, formula (III) shown in propiodal, formula (II)
The ratio between amount for the substance that feeds intake of base benzotriazole ranging from 1:0.5-1:2-4:1.2-2 (preferably 1：0.5：2：1.2)；
(2) acetyl bromide is added into reaction solution A obtained by step (1), the reaction was complete at room temperature, and gained reaction solution B is after
Processing obtains the bromo- 1- iodine dihalo objects of 2-；The addition of the acetyl bromide and olefin(e) compound shown in formula (I)
The ratio between amount of substance is 4-6:1 (preferably 5:1)；
In formula (I) or formula (IV)：
R1For substituted-phenyl, naphthalene or C1-8Alkyl；The substituted-phenyl is by halogen, nitro, C1-5Alkyl, C1-5Formic acid
Ester group or the phenyl of cyano substitution.
Further, in step (1), substituted olefine shown in the preferably described formula (I) is selected from one of following：Styrene, 2- first
Base styrene, 3- chlorostyrenes, 4- fluorobenzene ethenes, 4- cyano styrenes, 4- nitrostyrolenes, 4- methyl styrenes, propenyl benzene,
Naphthalene, indenes, amyl- 4- alkene -1- yl benzoic acids ester or octene.
Further, substituted olefine shown in the preferably described formula (I) is selected from one of following：Styrene, 3- chlorostyrenes, 4-
Nitrostyrolene, 4- cyano styrenes, amyl- 4- alkene -1- yl benzoic acid esters.
Further, substituted olefine shown in the preferably described formula (I) is selected from one of following：Styrene, 3- chlorostyrenes or
4- nitrostyrolenes.
Further, in step (1), the propiodal is elemental iodine.
Further, in step (1), the organic solvent is dichloromethane or 1,2- dichloromethane.
Further, in step (1), the volumetric usage of the organic solvent shown in the formula (I) to replace alkene
The ratio between amount of substance of hydrocarbon compound is 3-3.3ml/mmol.
Further, in step (1), preferred reaction time 4-6h.
Further, in step (2), preferred reaction time 10-16h.
Further, in step (2), the post-processing approach of the reaction solution B is：After reaction, by reaction solution elder generation
Carry out being concentrated under reduced pressure to give grease, gained grease carries out column chromatography for separation again, with volume ratio for 6/1-20/1 petroleum ether/
Ethyl acetate mixtures are eluant, eluent, collect the eluent containing target compound, are dried to get the 2- after solvent is evaporated off
Bromo- 1- iodine dihalo object.
Further, more specifically, synthetic method of the present invention is prepared in accordance with the following steps：
(1) by tert-butyl hydroperoxide, formula shown in substituted olefine compound shown in formula (I) and propiodal, formula (II)
(III) N- hydroxy benzo triazoles shown in are mixed in organic solvent, react 4-6h at 40 DEG C, obtain reaction solution A；It is described
Substituted olefine compound shown in formula (I) and N- hydroxyls shown in tert-butyl hydroperoxide, formula (III) shown in propiodal, formula (II)
The ratio between amount for the substance that feeds intake of base benzotriazole is 1：0.5：2：1.2；Substituted olefine shown in the formula (I) is selected from following
One of：Styrene, 2-methyl styrene, 3- chlorostyrenes, 4- fluorobenzene ethenes, 4- cyano styrenes, 4- nitrostyrolenes, 4- first
Base styrene, propenyl benzene, naphthalene, indenes, amyl- 4- alkene -1- yl benzoic acids ester or octene；The propiodal is elemental iodine；The solvent
For dichloromethane or 1,2- dichloroethanes；The volumetric usage of the solvent is to replace the object of acetylene hydrocarbon compound shown in formula (I)
The amount of matter is calculated as 3-3.3ml/mmol；
(2) acetyl bromide is added into reaction solution A obtained by step (1), reacts 10-16h at room temperature, it after reaction will be anti-
It answers liquid B first to carry out being concentrated under reduced pressure to give grease, gained grease is subjected to column chromatography for separation again, with volume ratio 6/1-20/1's
Petrol ether/ethyl acetate mixed liquor is eluant, eluent, collects and merge the eluent containing target compound, and drying after solvent is evaporated off,
Up to the bromo- 1- iodine dihalo objects of 2-；The object of the addition of the acetyl bromide and olefin(e) compound shown in formula (I)
The ratio between amount of matter is 5:1.
Compared with prior art, the beneficial effects of the invention are as follows：
(1) safety and environmental protection does not generate exhaust gas, more conducively its application in medicine synthesizes；
(2) compared with prior art, reaction condition is mild, and substrate adaptability is good, and a variety of substituent groups can be realized accordingly
The bromo- 1- iodine dihalo objects of 2-；
(3) directly using substituted olefine compound as raw material, whole process uses one kettle way, and operation is simple, is a kind of
Synthesize the variation route of the bromo- 1- iodine dihalide compounds containing various difference 2-.
(4) specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, but protection scope of the present invention and not only
It is limited to this.
Embodiment 1
By styrene (114.9 μ L, 1mmol), 70% tert-butyl hydroperoxide of iodine (26.9mg, 0.5mmol)
(257.5mg, 2mmol) and N- hydroxy benzo triazoles (166.6mg, 1.2mmol) are mixed in 3ml dichloromethane solvents and add
Enter into flask, reacts 4h at 40 DEG C.TLC is detected after reaction, is down to room temperature, be added acetyl bromide (202.2 μ L,
16h 5mmol) is reacted, TLC is detected after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated (bromo- 1- of 2-
Iodoethane base) benzene (compound 1) 117.7mg, yield 56.2%.
Characterization of The Products：White solid, m.p.60 DEG C.1H NMR(500MHz,CDCl3) δ 7.39 (tdd, J=8.6,5.6,
3.2Hz, 5H), 5.15 (dd, J=10.7,5.4Hz, 1H), 4.12-4.00 (m, 2H)13C NMR(125MHz,CDCl3)δ
138.63,129.20,128.88,127.67, 50.89,35.03.HRMS(ESI)calcd for C8H8BrI(M+H+):
310.96,found 309.89.
Embodiment 2
By p-nitrophenyl ethylene (44.7mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), 70% tertiary butyl mistake
Hydrogen oxide (77.25mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane
Solvent is added in flask, reacts 6h at 40 DEG C.TLC is detected after reaction, is down to room temperature, and acetyl bromide (121.33 μ are added
L, 1.5mmol) 16h is reacted, TLC is detected after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 1-
(the bromo- 1- iodoethane bases of 2-) -4- nitrobenzenes (compound 2) 68.6mg, yield 64.2%.
Characterization of The Products：Faint yellow solid, m.p.79 DEG C.1H NMR(500MHz,CDCl3)δ 8.30–8.22(m,2H),
7.62-7.56 (m, 2H), 5.17 (dd, J=11.3,4.9Hz, 1H), 4.13-3.94 (m, 2H)13C NMR(125MHz,
CDCl3)δ148.06,145.50, 128.83,124.12,47.78,33.88.HRMS(ESI)calcd for C8H7BrINO2
(M+H+):355.96,found 354.87.
Embodiment 3
By 3- chlorostyrenes (43.3mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), 70% t-butyl peroxy
It is molten that change hydrogen (77.25mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane
Agent is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, is down to room temperature, be added acetyl bromide (121.3 μ L,
16h 1.5mmol) is reacted, TLC is detected after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 1- is chloro-
3- (the bromo- 2- iodoethane bases of 1-) benzene (compound 3) 68.1mg, yield 65.7%.
Characterization of The Products：White solid, m.p.95 DEG C.1H NMR(500MHz,CDCl3) δ 7.40 (d, J=0.9Hz, 1H),
7.33 (dd, J=3.8,1.7Hz, 2H), 7.29 (ddd, J=7.4,4.5,1.3Hz, 1H), 5.07 (dd, J=11.0,
5.1Hz,1H),4.08–3.94(m,2H).13C NMR(126MHz,CDCl3)δ140.56,134.68,130.10,129.36,
127.91, 125.91,49.30,34.56.HRMS(ESI)calcd for C8H7BrClI(M+H+):345.40, found
343.85.
Embodiment 4
By naphthalene ethylene (15.4mg, 0.1mmol), iodine (12.7mg, 0.05mmol), tert-butyl hydroperoxide
(25.7mg, 0.2mmol) and N- hydroxy benzo triazoles (13.6 mg, 0.12mmol) are mixed in 0.5ml dichloromethane solvents
It is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, and acetyl bromide (40.4 μ L, 0.5mmol) is added and reacts
12h, TLC are detected after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 2- (the bromo- 1- iodine ethyls of 2-)
Naphthalene (compound 4) 11.7mg, yield 32.4%.
Characterization of The Products：White solid, m.p.94 DEG C.1H NMR(500MHz,CDCl3) δ 7.89 (d, J=8.6Hz, 1H),
7.87-7.83 (m, 3H), 7.55-7.49 (m, 3H), 5.34 (dd, J=9.6,6.5Hz, 1H), 4.18-4.11 (m, 2H)13C
NMR(125MHz,CDCl3)δ 135.72,133.53,132.93,129.12,128.22,127.81,127.46,126.94,
126.72, 124.37,51.35,34.80.HRMS(ESI)calcd forC12H10BrI(M+H+):361.02, found
359.90.
Embodiment 5
By 4- fluorobenzene ethenes (37.7mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), 70% t-butyl peroxy
It is molten that change hydrogen (77.25mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane
Agent is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, and it is anti-that acetyl bromide (121.3 μ L, 5mmol) is added
16h, TLC is answered to detect after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 1- (bromo- 1- iodoethylenes of 2-
Base) -4- fluorobenzene ethenes and (compound 5) 41.7mg, yield 42.0%.
Characterization of The Products：White solid, m.p.77 DEG C.1H NMR(500MHz,CDCl3)δ7.42 –7.36(m,2H),7.07
(t, J=8.6Hz, 2H), 5.13 (dd, J=11.1,5.1Hz, 1H), 4.10-3.94 (m, 2H)13C NMR(125MHz,
CDCl3) δ 163.84 (s), 161.86 (s), 134.57 (d, J=3.4Hz), 129.55 (d, J=8.4Hz), 116.01 (s),
115.84(s), 49.81(s),35.00(s)HRMS(ESI)calcd for C8H7BrFI(M+H+):328.95, found
327.88.
Embodiment 6
By 2-methyl styrene (36.2mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), tert-butyl hydroperoxide
Hydrogen (77.2mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane solvents
It is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, and it is anti-that acetyl bromide (121.3 μ L, 1.5mmol) is added
16h, TLC is answered to detect after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 1- (2-bromo- 1- iodine second
Base) 21.0 mg of -2- toluene (compound 6), yield 25.1%.
Characterization of The Products：White liquid.1H NMR(500MHz,CDCl3) δ 7.47-7.44 (m, 1H), 7.26 (ddt, J=
13.6,8.8,3.8Hz, 2H), 7.19 (d, J=7.0Hz, 1H), 5.45 (dd, J=9.6,6.7Hz, 1H), 4.13 (dd, J=
10.1,3.6Hz,2H),2.42(s, 3H).13C NMR(125MHz,CDCl3) δ 136.49 (d, J=14.2Hz), 130.87
(s), 129.00(s),126.86(s),126.26(s),46.83(s),34.16(s),19.24(s).HRMS (ESI)calcd
for C9H10BrI(M+H+):324.98,found 323.90.
Embodiment 7
By amyl- 4- alkene -1- yl benzoic acids ester (57.1mg, 0.3mmol), iodine (38.1 mg, 0.15mmol), tertiary fourth
Base hydrogen peroxide (77.2mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloros
Methane solvent is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, addition acetyl bromide (121.3 μ L,
16h 1.5mmol) is reacted, TLC is detected after reaction, with column chromatography chromatogram method (eluent：Petrol ether/ethyl acetate=9/1)
Isolated bromo- 4- iodine amyl benzoic ether (compound 7) 70.8mg of 5-, yield 59.4%.
Characterization of The Products：Weak yellow liquid.1H NMR(500MHz,CDCl3) δ 8.05 (dd, J=8.3,1.3Hz, 2H),
7.59-7.54 (m, 1H), 7.48-7.42 (m, 2H), 4.38 (t, J=6.1Hz, 2H), 4.24 (ddt, J=9.0,7.7,
3.6Hz, 1H), 3.88 (dd, J=10.3,4.3 Hz, 1H), 3.64 (t, J=10.2Hz, 1H), 2.44-2.32 (m, 1H),
2.13–2.04(m, 1H),2.00–1.87(m,2H).13C NMR(125MHz,CDCl3)δ166.52,133.01, 130.15,
129.58,128.40,\63.87,51.96,35.92,32.78,26.25.HRMS(ESI) calcd for C12H14BrIO2(M+
H+):397.05,found 395.92.
Embodiment 8
By 4- cyano styrenes (38.7mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), tert-butyl hydroperoxide
Hydrogen (77.2mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane solvents
It is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, and it is anti-that acetyl bromide (121.3 μ L, 1.5mmol) is added
16h, TLC is answered to detect after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 4- (2-bromo- 1- iodine second
Base) benzonitrile (compound 8) 61.2mg, yield 61.3%.
Characterization of The Products：Brown oil.1H NMR(500MHz,CDCl3) δ 7.70-7.65 (m, 2H), 7.51 (d, J=
8.3Hz, 2H), 5.12 (dd, J=11.2,4.9Hz, 1H), 4.09-3.93 (m, 2H)13C NMR(125MHz,CDCl3)δ
143.54,132.57,128.50, 118.12,112.84,48.33,33.89.HRMS(ESI)calcd for C9H7BrIN(M+
H+):335.88,found 334.88.
Embodiment 9
By indenes (61.1mg, 0.5mmol), iodine (63.4mg, 0.25mmol), tert-butyl hydroperoxide (128.7mg,
1mmol) and N- hydroxy benzo triazoles (83.3 mg, 0.6mmol) are mixed in 2ml dichloromethane solvents and are added in flask,
4h is reacted at 40 DEG C.TLC is detected after reaction, and acetyl bromide (202.2 μ L, 2.5mmol) is added and reacts 16h, TLC detections
After reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 2-bromo- iodo- 2, the 3- dihydros-1H- indenes of 1- (changes
Close object 9) 51.2mg, yield 31.7%.
Characterization of The Products：Colourless liquid.1H NMR(500MHz,CDCl3) δ 7.49 (dd, J=5.6,3.3Hz, 1H), 7.38-
7.30 (m, 3H), 5.65 (s, 1H), 4.89 (dt, J=5.2,1.0 Hz, 1H), 3.88-3.23 (m, 2H)13C NMR
(125MHz,CDCl3)δ140.57, 129.72,127.96,125.72,125.42,57.73,54.45,41.44.HRMS
(ESI)calcd for C9H8BrI(M+H+):322.97,found 321.89.
Embodiment 10
By octene (68.7mg, 0.6mmol), iodine (76.2mg, 0.3mmol), tert-butyl hydroperoxide (154.5mg,
1.2mmol) and N- hydroxy benzo triazoles (99.3 mg, 7.2mmol) are mixed in 2ml dichloromethane solvents and are added to flask
In, react 4h at 40 DEG C.TLC is detected after reaction, and chloroacetic chloride (353.6 μ L, 3mmol) is added and reacts 16h, TLC detections
After reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated bromo- 1- iodo-octanes (compound 10) of 2-
79.4mg, yield 41.5%.
Characterization of The Products：Colourless liquid.1H NMR(500MHz,CDCl3)δ4.25–4.09(m, 1H),3.88–3.71(m,
1H), 3.66-3.48 (m, 1H), 2.14 (dtdd, J=13.7,10.4,5.6,3.2Hz, 1H), 1.82-1.73 (m, 1H),
1.56 (qd, J=10.2,5.0Hz, 1H), 1.39-1.26 (m, 7H), 0.89 (t, J=6.8Hz, 3H)13C NMR(125MHz,
CDCl3) δ53.17(s),36.37(s),36.04(s),31.59(s),28.49(s),26.72(s),22.56(s), 14.06
(s).HRMS(ESI)calcd for C8H16BrI(M+H+):319.02,found 317.95.
Embodiment 11
By propenyl benzene (60.3mg, 0.5mmol), iodine (63.4mg, 0.25mmol), tert-butyl hydroperoxide
(128.7mg, 1mmol) and N- hydroxy benzo triazoles (83.3 mg, 0.6mmol) are mixed in the addition of 2ml dichloromethane solvents
Into flask, 4h is reacted at 40 DEG C.TLC is detected after reaction, and acetyl bromide (202.2 μ L, 3mmol) is added and reacts 16h,
TLC is detected after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated (the bromo- 2- iodine propyl of 3-) benzene (changes
Close object 11) 82.1mg, yield 50.5%.
Characterization of The Products：Colourless liquid.1H NMR(500MHz,CDCl3) δ 7.37-7.34 (m, 2H), 7.31 (dd, J=
7.0,4.9Hz, 3H), 4.42-4.35 (m, 1H), 3.84 (dd, J=10.5,4.2Hz, 1H), 3.65 (dd, J=10.4,
9.0Hz, 1H), 3.52 (dd, J=14.5,4.8 Hz, 1H), 3.15 (dd, J=14.5,7.8Hz, 1H)13C NMR(125MHz,
CDCl3)δ 136.82,129.49,128.49,127.18,52.42,41.96,36.05.HRMS(ESI)calcd for
C9H10BrI(M+H+):324.98,found 323.90.
Embodiment 12
By 4- methyl styrenes (36.2mg, 0.3mmol), iodine (38.1mg, 0.15 mmol), tert-butyl hydroperoxide
Hydrogen (77.2mg, 0.6mmol) and N- hydroxy benzo triazoles (49.1mg, 0.36mmol) are mixed in 1ml dichloromethane solvents
It is added in flask, reacts 4h at 40 DEG C.TLC is detected after reaction, and it is anti-that acetyl bromide (121.3 μ L, 1.5mmol) is added
16h, TLC is answered to detect after reaction, with column chromatography chromatogram method (eluent：Petroleum ether) isolated 1- (2-bromo- 1- iodine second
Base) -4- toluene (compound 12) 30.6mg, yield 31.4%.
Characterization of The Products：Pale white solid, m.p.65 DEG C.1H NMR(500MHz,CDCl3) δ 7.30 (d, J=8.1Hz,
2H), 7.20 (d, J=8.0Hz, 2H), 5.15 (dd, J=10.7,5.4Hz, 1H), 4.12-3.97 (m, 2H), 2.37 (s,
3H).13C NMR(125MHz, CDCl3)δ139.28,135.67,129.60,127.53,51.06,35.07,21.31.HRMS
(ESI)calcd for C9H10BrI(M+H+):324.98,found 323.90。
Claims (10)
1. the synthetic method of the bromo- 1- iodine dihalo objects of 2- shown in a kind of formula (IV), it is characterised in that：The synthetic method tool
Body is prepared in accordance with the following steps：
(1) by tert-butyl hydroperoxide, formula (III) institute shown in substituted olefine compound shown in formula (I) and propiodal, formula (II)
The N- hydroxy benzo triazoles shown are dissolved in organic solvent, and in room temperature at 50 DEG C, the reaction was complete obtains reaction solution A；The formula
(I) substituted olefine compound shown in and N- hydroxy benzenes shown in tert-butyl hydroperoxide, formula (III) shown in propiodal, formula (II)
And the ratio between amount for the substance that feeds intake of triazole is 1:0.5-1:2-4:1.2-2；
(2) acetyl bromide is added into reaction solution A obtained by step (1), the reaction was complete at room temperature, and gained reaction solution B is post-treated
Obtain the bromo- 1- iodine dihalo objects of 2-；The substance of the addition of the acetyl bromide and olefin(e) compound shown in formula (I)
The ratio between amount be 4-6:1；
In formula (I) or formula (IV)：
R1For substituted-phenyl, naphthalene or C1-8Alkyl；The substituted-phenyl is by halogen, nitro, C1-5Alkyl, C1-5Formic acid ester group or
The phenyl of cyano substitution.
2. synthetic method as described in claim 1, it is characterised in that：In step (1), substituted olefine shown in the formula (I)
Selected from one of following：Styrene, 2-methyl styrene, 3- chlorostyrenes, 4- fluorobenzene ethenes, 4- cyano styrenes, 4- nitrobenzenes
Ethylene, 4- methyl styrenes, propenyl benzene, naphthalene, indenes, amyl- 4- alkene -1- yl benzoic acids ester or octene.
3. synthetic method as claimed in claim 2, it is characterised in that：In step (1), substituted olefine shown in the formula (I)
Selected from one of following：Styrene, 3- chlorostyrenes, 4- nitrostyrolenes, 4- cyano styrenes or amyl- 4- alkene -1- yl benzoic acids
Ester.
4. synthetic method as described in claim 1, it is characterised in that：In step (1), the propiodal is elemental iodine.
5. synthetic method as described in claim 1, it is characterised in that：In step (1), the organic solvent is dichloromethane
Or 1,2- dichloromethane.
6. the synthetic method as described in claim 1 or 5, it is characterised in that：In step (1), the volume of the organic solvent
Dosage is calculated as 3-3.3ml/mmol with the amount of the substance of substituted olefine compound shown in the formula (I).
7. synthetic method as described in claim 1, it is characterised in that：In step (1), reaction time 4-6h.
8. synthetic method as described in claim 1, it is characterised in that：In step (2), reaction time 10-16h.
9. synthetic method as described in claim 1, it is characterised in that：In step (2), the post-processing side of the reaction solution B
Method is：After reaction, reaction solution first being carried out being concentrated under reduced pressure to give grease, gained grease carries out column chromatography for separation again,
Using volume ratio for 6/1-20/1 petrol ether/ethyl acetate mixed liquor as eluant, eluent, collect the eluent containing target compound, steam
Except dry to get the bromo- 1- iodine dihalo objects of 2- after solvent.
10. the synthetic method as described in one of claim 1~9, it is characterised in that：The synthetic method in accordance with the following steps into
It is prepared by row：
(1) by tert-butyl hydroperoxide, formula (III) institute shown in substituted olefine compound shown in formula (I) and propiodal, formula (II)
The N- hydroxy benzo triazoles shown are mixed in organic solvent, react 4-6h at 40 DEG C, obtain reaction solution A；Formula (I) institute
The substituted olefine compound shown and N- hydroxy benzos three shown in tert-butyl hydroperoxide, formula (III) shown in propiodal, formula (II)
The ratio between amount for the substance that feeds intake of nitrogen azoles is 1：0.5：2：1.2；Substituted olefine shown in the formula (I) is selected from one of following：Benzene second
Alkene, 2-methyl styrene, 3- chlorostyrenes, 4- fluorobenzene ethenes, 4- cyano styrenes, 4- nitrostyrolenes, 4- methyl styrenes,
Propenyl benzene, naphthalene, indenes, amyl- 4- alkene -1- yl benzoic acids ester or octene；The propiodal is elemental iodine；The solvent is dichloromethane
Or 1,2- dichloroethanes；The volumetric usage of the solvent shown in formula (I) to replace the amount of the substance of acetylene hydrocarbon compound to be calculated as
3-3.3ml/mmol；
(2) acetyl bromide is added into reaction solution A obtained by step (1), 10-16h is reacted at room temperature, after reaction by reaction solution
B first carries out being concentrated under reduced pressure to give grease, gained grease is carried out column chromatography for separation again, with the oil of volume ratio 6/1-20/1
Ether/ethyl acetate mixtures are eluant, eluent, collect and merge the eluent containing target compound, be evaporated off after solvent dry to get
The bromo- 1- iodine dihalo objects of the 2-；The amount of the addition of the acetyl bromide and the substance of olefin(e) compound shown in formula (I)
The ratio between be 5:1.
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| CN111875470A (en) * | 2020-08-17 | 2020-11-03 | 苏州正济药业有限公司 | Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin |
| CN114805044A (en) * | 2021-01-19 | 2022-07-29 | 兰州大学 | Novel method for synthesizing dibromo compound |
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| CN111875470B (en) * | 2020-08-17 | 2023-02-03 | 苏州正济药业有限公司 | Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin |
| CN114805044A (en) * | 2021-01-19 | 2022-07-29 | 兰州大学 | Novel method for synthesizing dibromo compound |
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