CN106831673A - The preparation method of Amiodarone Hydrochloride intermediate 2 butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3,5) benzofuran - Google Patents
The preparation method of Amiodarone Hydrochloride intermediate 2 butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3,5) benzofuran Download PDFInfo
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- CN106831673A CN106831673A CN201710039161.5A CN201710039161A CN106831673A CN 106831673 A CN106831673 A CN 106831673A CN 201710039161 A CN201710039161 A CN 201710039161A CN 106831673 A CN106831673 A CN 106831673A
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- Prior art keywords
- butyl
- benzofuran
- diiodo
- benzoyl
- hydroxyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
Abstract
Present invention is disclosed the preparation method of a kind of Amiodarone Hydrochloride intermediate 2 butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3,5) benzofuran, by iodine and 2 butyl 3 (4 (2-hydroxybenzoyl)) benzofurans in molar ratio 1.0~4.0：1 mixing, with solvent room temperature reaction 15~50 hours in the presence of acid binding agent, solvent is C1~6 aliphatic alcohols solvent, and butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3, the 5) benzofuran of Amiodarone Hydrochloride intermediate 2 is obtained.Implement above-mentioned technical proposal of the invention, by raw material selection, proportioning, the selection of acid binding agent and the reasonable control of reaction condition, compared to the manufacturing route of prior art, improve operation ease, product quality stability, and it is suitable to put into large-scale industrial production, increases the production capacity of product.
Description
Technical field
The present invention relates to a kind of preparation method of antiarrhythmic drug intermediate, and in particular in a kind of Amiodarone Hydrochloride
The preparation method of mesosome 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran.
Background technology
Amiodarone Hydrochloride (ADHC) is one of antiarrhythmic drug the most frequently used at present, is clinically mainly used in supraventricular
And ventricular tachyarrhythmia, various organic heart diseasies, acute coronary syndrome etc. are also used for, can be used as there is symptom
Property atrial fibrillation is not complete with left chamber function or first-line treatment medication of chronic heart failure.
Arrhythmia cordis is clinical common disease, and it both can individually occur be occurred together with cardiovascular disease, it might even be possible to
Break out and cause sudden death, be always treatment problem clinically.ADHC, Xinluning tablet and procaine are treatment arrhythmia cordis
Common drug, but proarrhythmia incidence is different while its anti-arrhythmia, therefore, clinically select relative peace
Complete effective antiarrhythmic drug it is critical that.ADHC can reduce generation and the arrhythmic deaths of VA
Danger, its arrhythmogenic effect is small, and negative inotropic action is light or nothing, and with anti-ischemic effect, conduction hinders generating chamber in
Stagnant, these are all not available for other antiarrhythmic drugs.ADHC turned into AMI with room property tachyarrhythmia,
The choice drug that ventricular arythmia, heart failure prevent with arrhythmia cordis, sudden cardiac death after infarct.
2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran is the important centre of Amiodarone Hydrochloride (ADHC)
Body.The technical measures of the preparation of the intermediate can be divided into following a few classes：
1. organic base heating response utilized, such as Russ P 2186063, with sodium acetate and sodium acid carbonate as acid binding agent,
The operation for flowing back in methyl alcohol carrys out iodo.But high temperature reduces the selectivity of iodo, while reducing reaction yield.
2. with NaOH as acid binding agent, with elemental iodine, 0 degree is reacted United States Patent (USP) US 6103708, the yield of bearing reaction
Only 47%.Low yield limits the use of the method.
3. Chinese patent CN1858042 increases iodo efficiency with potassium carbonate as acid binding agent by the method for hydrogen peroxide oxidation,
But reaction needs to be carried out under the heating of 80-85 degree, and iodo is selectively bad.
The content of the invention
In view of the defect that above-mentioned prior art is present, the purpose of the present invention is to propose to a kind of Amiodarone Hydrochloride intermediate 2- fourths
The preparation method of base -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran, solves the difficulty of Amiodarone Hydrochloride course of industrialization
Point.
Above-mentioned purpose of the invention, its technical solution being achieved is：A kind of Amiodarone Hydrochloride intermediate 2- fourths
The preparation method of base -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran, it is characterised in that：By iodine and 2- butyl -3- (4-
(2-hydroxybenzoyl)) benzofuran in molar ratio 1.0~4.0：1 mixing, with solvent room temperature in the presence of oxidant and acid binding agent
Reaction 15~50 hours, solvent is C1~6 aliphatic alcohols solvent, and Amiodarone Hydrochloride intermediate 2- butyl -3- (4- hydroxyls are obtained
Base -3,5- diiodo-s benzoyl) benzofuran.
As the further prioritization scheme of above-mentioned technical proposal：Wherein described acid binding agent is potassium carbonate, sodium carbonate, hydroxide
Potassium, the one kind in NaOH.
The application implementation of technical solution of the present invention, compared to the manufacturing route of prior art, with following notable
Visible effect：By raw material selection, proportioning, the selection of catalyst and the reasonable control of reaction condition, salt acid amide iodine is simplified
The production technology of ketone intermediate 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran, improve operation ease,
Product quality stability, and be suitable to put into large-scale industrial production, increase the production capacity of product.Reaction is entered at normal temperatures
OK, the energy is saved, while compared with 0 DEG C and pyroreaction, iodo selectivity and reaction yield are improved largely, and have
Save cost to effect.
Specific embodiment
Below just in conjunction with the embodiments, specific embodiment of the invention is described in further detail, so that the technology of the present invention
Scheme is more readily understood, grasps.
Embodiment 1：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), 124 grams of potassium carbonate
(0.9mol), 453 grams sumptuous (1.7mol) is put into 5 liters of reaction bulbs, plus 2 kilograms of methyl alcohol, complete molten, the room temperature reaction 50 hours of stirring.
PH=1, suction filtration, washing filter cake is adjusted to obtain final product faint yellow 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzo furan with concentrated hydrochloric acid
Mutter, be vacuum dried to obtain 811 grams of dry product, yield is 87.3%.Obtained product elementary analysis is as follows：Theoretical value：C, 41.78%；
H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.77%；H, 2.96%；I, 46.50%；O, 8.76%
Embodiment 2：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), 50.4 grams of potassium hydroxide
(0.9mol), 1132.5 grams sumptuous (4.25mol) is put into 5 liters of reaction bulbs, plus 2 kg ethanols, and stirring is complete molten, and room temperature reaction 30 is small
When.PH=1, suction filtration, washing filter cake is adjusted to obtain final product faint yellow 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzene with concentrated hydrochloric acid
And furans, 832 grams of dry product is vacuum dried to obtain, yield is 89.6%.Obtained product elementary analysis is as follows：Theoretical value：C,
41.78%；H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.79%；H, 2.97%；I, 46.47%；O,
8.75%
Embodiment 3：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), 36 grams of NaOH
(0.9mol), 1812 grams sumptuous (6.8mol) is put into 5 liters of reaction bulbs, plus 2 kilograms of propyl alcohol, complete molten, the room temperature reaction 15 hours of stirring.
PH=1, suction filtration, washing filter cake is adjusted to obtain final product faint yellow 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzo furan with concentrated hydrochloric acid
Mutter, be vacuum dried to obtain 827 grams of dry product, yield is 89.1%.Obtained product elementary analysis is as follows：Theoretical value：C, 41.78%；
H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.78%；H, 2.96%；I, 46.47%；O, 8.78%
Embodiment 4：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), 36 grams of NaOH
(0.9mol), 1132.5 grams sumptuous (4.25mol) is put into 5 liters of reaction bulbs, plus 2 kilograms of propyl alcohol, and stirring is complete molten, and room temperature reaction 15 is small
When.PH=1, suction filtration, washing filter cake is adjusted to obtain final product faint yellow 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzene with concentrated hydrochloric acid
And furans, 829 grams of dry product is vacuum dried to obtain, yield is 89.3%.Obtained product elementary analysis is as follows：Theoretical value：C,
41.78%；H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.80%；H, 2.94%；I, 46.47%；O,
8.78%
Embodiment 5：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), potassium hydroxide 50.4
Gram, 60 grams of potassium carbonate, 1132.5 grams sumptuous (4.25mol) is put into 5 liters of reaction bulbs, plus 2 kg ethanols, propanol mixture, stirring
Quan Rong, room temperature reaction 30 hours.With concentrated hydrochloric acid adjust pH=1, suction filtration, washing filter cake obtain final product faint yellow 2- butyl -3- (4- hydroxyls -
3,5- diiodo- benzoyls) benzofuran, 834 grams of dry product is vacuum dried to obtain, yield is 89.8%.Obtained product elementary analysis is such as
Under：Theoretical value：C, 41.78%；H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.80%；H, 2.94%；I,
46.45%；O, 8.80%
Embodiment 6：By 2- butyl -3- (4- (2-hydroxybenzoyl)s) 500 grams of benzofuran (1.7mol), 25 grams of potassium hydroxide
(0.9mol), 1132.5 grams sumptuous (4.25mol) is put into 5 liters of reaction bulbs, plus 2 kg ethanols, and stirring is complete molten, and room temperature reaction 30 is small
When.PH=1, suction filtration, washing filter cake is adjusted to obtain final product faint yellow 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzene with concentrated hydrochloric acid
And furans, 832 grams of dry product is vacuum dried to obtain, yield is 89.6%.Obtained product elementary analysis is as follows：Theoretical value：C,
41.78%；H, 2.95%；I, 46.47%；O, 8.79%；Measured value：C, 41.80%；H, 2.95%；I, 46.45%；O,
8.79%.
Claims (1)
1. a kind of preparation method of Amiodarone Hydrochloride intermediate 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran,
It is characterized in that：By iodine and 2- butyl -3- (4- (2-hydroxybenzoyl)s) benzofuran in molar ratio 1.0~4.0：1 mixing, is tiing up acid
With solvent room temperature reaction 15~50 hours in the presence of agent, solvent is C1~6 aliphatic alcohols solvent, is obtained in Amiodarone Hydrochloride
Mesosome 2- butyl -3- (4- hydroxyl -3,5- diiodo-s benzoyl) benzofuran, described acid binding agent is potassium carbonate, sodium carbonate, hydrogen-oxygen
Change the one kind in potassium, NaOH.
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| CN201710039161.5A CN106831673A (en) | 2017-01-19 | 2017-01-19 | The preparation method of Amiodarone Hydrochloride intermediate 2 butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3,5) benzofuran |
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| CN201710039161.5A CN106831673A (en) | 2017-01-19 | 2017-01-19 | The preparation method of Amiodarone Hydrochloride intermediate 2 butyl 3 (the diiodo- benzoyl of 4 hydroxyl 3,5) benzofuran |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
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Application publication date: 20170613 |