CN109053652A - A kind of preparation method of Amiodarone Hydrochloride intermediate - Google Patents
A kind of preparation method of Amiodarone Hydrochloride intermediate Download PDFInfo
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- CN109053652A CN109053652A CN201811023839.1A CN201811023839A CN109053652A CN 109053652 A CN109053652 A CN 109053652A CN 201811023839 A CN201811023839 A CN 201811023839A CN 109053652 A CN109053652 A CN 109053652A
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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
The invention belongs to pharmaceutical synthesis fields；A kind of preparation method of Amiodarone Hydrochloride intermediate, it is characterised in that the following steps are included: 1) compound 1 under alkaline condition nucleophilic substitution occurs with compound 2 in the presence of a phase transfer catalyst and obtains compound 3；2) compound 3 hydrolyzes under alkaline condition generates compound 4；3) by intramolecular aldol condensation, decarboxylation is dehydrated to obtain compound 5 compound 4 again；4) compound 6 is reacted with thionyl chloride heating generates compound 7；5) compound 5 obtains compound 8 with the generation friedel-crafts acylation reaction of compound 7 in the presence of a lewis acid；6) demethylation generates compound 9, i.e. Amiodarone Hydrochloride intermediate 2- butyl -3- (4- hydroxy benzoyl) benzofuran to compound 8 in the presence of a lewis acid.A kind of preparation method of Amiodarone Hydrochloride intermediate of the present invention has the advantages that the reaction time is short, product purity is high, high income, is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation methods of antiarrhythmic drug Amiodarone Hydrochloride intermediate, and in particular to 2- fourth
The preparation method of base -3- (4- hydroxy benzoyl) benzofuran, belongs to pharmaceutical synthesis field.
Background technique
Amiodarone Hydrochloride is that current clinical application is most, widest antiarrhythmic drug.In addition, Amiodarone Hydrochloride
Due to stable curative effect, lesser side effect, to become the long-term administration of patients with arrhythmia first choice.Today's society, people
Work rhythm is constantly reinforced, and the pressure faced constantly increases, and the patient of cardiovascular disease is continuously increased, antiarrhythmic drug
The market share of the jumbo promotion of demand, Amiodarone Hydrochloride will continue growing.
2- butyl -3- (4- hydroxy benzoyl) benzofuran is the important intermediate of Amiodarone Hydrochloride.Patent
CN104262304 is starting material with compound 1,2, and the compound 3 of generation is under conditions of sodium methoxide does alkali, toluene makees solvent
Reaction generates compound 5；Compound 5, which reacts under the conditions of lewis acid with compound 7, generates compound 8；Compound 8 is in Louis
It is hydrolyzed under the conditions of this acid, reaction generates 2- butyl -3- (4- hydroxy benzoyl) benzofuran 9.
The synthetic route has the disadvantage in that compound 3 under conditions of sodium methoxide does alkali, toluene makees solvent, although can
Compound 5 is directly obtained to need not move through hydrolysis, but since the difficulty of piptonychia ester is much larger compared with decarboxylation difficulty, leads to generationization
The annulation conversion ratio for closing object 5 is low, and by-product is more, and separation is difficult；It is low so as to cause total recovery, increased costs.
The synthetic route of patent CN107382925 report, in addition to by the route of 3 prepare compound 5 of compound difference, remaining
Reaction route is all the same, only reaction condition different from.The aldehyde radical of compound 3 first uses trimethyl orthoformate in the reaction route
Protection, generate compound 0, later again with compound 0 hydrolyze prepare compound 4, compound 4 paratoluensulfonyl chloride catalysis under at
Ring obtains compound 5.
The route has the disadvantage in that in 3 prepare compound 5 of compound, increases trimethyl orthoformate and protects aldehyde radical, so
Ester group is first hydrolyzed afterwards into acid, then sloughs the protecting group of aldehyde radical；Though can reduce aldehyde radical occurs side reaction, reaction step is increased,
And trimethyl orthoformate height is inflammable, there is security risk.Compound 4 is catalyzed the reaction for generating compound 5 in paratoluensulfonyl chloride
Yield is lower, while also increasing cost.
Summary of the invention
The present invention explores in view of the above-mentioned problems, inventor carries out process optimization on the basis of with reference to the above two lines
A kind of preparation method of more efficient convenient Amiodarone Hydrochloride intermediate out, this method is easy to operate, and product yield is high, product matter
Amount and process stabilizing are suitble to industrialized production.
The technical solution adopted by the invention is as follows:
A kind of preparation method of Amiodarone Hydrochloride intermediate, it is characterised in that the following steps are included:
1) under the conditions of 20~30 DEG C, compound 1 and compound 2 are added into reaction dissolvent, and alkali, phase transfer catalysis (PTC) is added
Agent, temperature reaction；Desalination, filtrate washing are filtered after the reaction was completed, and organic phase is concentrated to dryness, and obtains oily compounds 3；
2) compound 3 plus lye, are stirred at room temperature hydrolysis；Adjust pH to faintly acid, extraction, drying after the reaction was completed；Organic phase
It is concentrated to dryness, obtains oily compounds 4；
3) compound 4 adds in solvent, and alkali and dehydrating agent, heating reaction is added；Reaction solution is poured into water after the reaction was completed,
Extraction, drying；Organic phase is concentrated to dryness, and obtains oily compounds 5；
4) compound 6 is added in solvent and thionyl chloride, temperature reaction, after the reaction was completed evaporating solvent under reduced pressure and residual chlorine
Change sulfoxide, obtains colourless solution compound 7；
5) solvent and lewis acid are added under low temperature, is added with stirring compound 7；It is stirring evenly and then adding into compound 5, is protected
Temperature reaction；Reaction solution is poured into water after the reaction was completed, adjusts pH to 2；Liquid separation, drying, evaporating solvent under reduced pressure obtain compound 8；
6) lewis acid temperature reaction is added after the dissolution of 8 solubilizer of compound；Reaction solution is poured into water after the reaction was completed, is adjusted
PH to 2；Liquid separation, drying；It is concentrated under reduced pressure into solid precipitation, cool down crystallization；It filters, wet product vacuum drying obtains off-white color crystallization
Property powdered compounds 9.
Preferably 60~100 DEG C of reaction temperature described in step 1) described above, more preferable 75~85 DEG C, the reaction time 1~2
Hour.
The preferred DMF of reaction dissolvent described in step 1) described above, ethyl acetate, toluene, more preferable ethyl acetate.
Alkali described in step 1) described above is sodium carbonate, potassium carbonate, cesium carbonate, more preferable cesium carbonate.
Phase transfer catalyst described in step 1) described above is that methyl tricapryl ammonium chloride dosage is 0.01~0.10 to rub
That equivalent, preferably 0.02 molar equivalent.
Cesium carbonate dosage described in step 1) described above is 0.2~1.0 molar equivalent, preferably 0.6 molar equivalent.
2 dosage of compound described in step 1) described above is 1.0~2.0 molar equivalents, preferably 1.2 molar equivalents.
Reaction temperature described in step 2) described above is preferably 20~30 DEG C, and the reaction time 0.5~1 hour.
The preferred water of reaction dissolvent described in step 2) described above, methanol, ethyl alcohol, more preferable water.
Reaction described in step 2) described above is sodium hydroxide, potassium hydroxide, lithium hydroxide, more preferable hydroxide with alkali
Sodium.
Base amount described in step 2) described above is 1~4 molar equivalent, preferably 3 molar equivalents.
Reaction temperature described in step 3) described above is preferably 90~100 DEG C, and the reaction time 1~2 hour.
Reaction dehydrating agent described in step 3) described above is acetic anhydride, and dosage is 2~8w/w, preferably 8w/w；Described
The preferred sodium acetate of reaction alkali, dosage are 2~4w/w, preferably 2.8w/w.
Reaction dissolvent described in step 4) described above is toluene.
Reaction dissolvent consumption described in step 4) described above is 1~10w/w, preferably 2~4w/w.
Thionyl chloride dosage described in step 4) described above is 1~4 molar equivalent, preferably 2.5 molar equivalents.
Preferably 60~100 DEG C of reaction temperature described in step 4) described above, more preferable 75~85 DEG C, the reaction time 2~4
Hour.
Charge temperature described in step 5) described above is -30~0 DEG C, preferably -20~-10 DEG C.
The preferred toluene of reaction dissolvent described in step 5) described above, 1,2- dichloroethanes, more preferable 1,2- dichloroethanes.
The preferred alchlor of lewis acid described in step 5) described above, alchlor dosage are 1~3 molar equivalent,
It is preferred that 1 molar equivalent.
Preferably 60~100 DEG C of reaction temperature described in step 6) described above, more preferable 80~90 DEG C, the reaction time 2~4
Hour.
The preferred alchlor of lewis acid described in step 6) described above, alchlor dosage are 1~3 molar equivalent,
It is preferred that 1.1 molar equivalents.
Beneficial effect
Innovation of the present invention:
The universal yield of the prior art is relatively low, total recovery 10~30%, and post-processing is cumbersome, it is more to generate the three wastes.For technique
The problem of, improvement is optimized such as to existing technique in the present invention:
1. (alkali is hydroxide to aqueous slkali at a temperature of using 20~30 DEG C in 3 prepare compound 4 of compound
Sodium, potassium hydroxide, lithium hydroxide) direct hydrolysis, rather than sodium methoxide does alkali, condition milder, reaction conversion in CN104262304
Rate is high, and occurs without side reaction；
2. not used in 4 prepare compound 5 of compound using acetic anhydride and sodium acetate catalysis, dehydration
The aldehyde radical of compound 3 is first protected with trimethyl orthoformate in CN107382925, deprotects process, but total recovery is higher than
CN107382925 is specifically shown in comparative example and compares 2 times more.
It investigates and is optimized 3. pair each step all materials re-start.
By improving above, reduces side reaction, improve yield, and post-processing is convenient easy to operate, effectively reduces three
Useless yield, is suitable for industrialized production.
For present invention process without especial equipment requirements, no special reaction parameter is easy to operate, and 10 feather weight works are completed at present
Skill verifying meets industrial mass production demand, and route total recovery reaches 40%~50%, and 98% or more purity meets inner quality standard.
Detailed description of the invention
Fig. 1 is 5 nuclear magnetic resonance spectroscopy of compound；
Fig. 2 is 5 carbon-13 nmr spectra of compound；
Fig. 3 is 9 nuclear magnetic resonance spectroscopy of compound；
Fig. 4 is 9 carbon-13 nmr spectra of compound.
Specific embodiment
Below with reference to embodiment and specific embodiment, the present invention is described in further detail.But this should not be understood
It is only limitted to embodiment below to invent the range of above-mentioned theme, it is all that this hair is belonged to based on the technology that the content of present invention is realized
Bright range.
Embodiment 1:
15.00kg (122.8mol, 1eq) compound 1 and 30.82kg (147.4mol, 1.2eq) compound 2 are added to
In 120.00kg (8w/w) ethyl acetate, addition 24.00kg (73.7mol, 0.6eq) cesium carbonate, 1.00kg (2.5mol,
0.02eq) methyl tricapryl ammonium chloride stirs and is warming up to 75~85 DEG C, reaction 1~2 hour.It filters after reaction, filtrate
60.00kg (4w/w) purified water is added to wash, 40 DEG C of organic phase are concentrated to dryness, 30.21kg (120.7mol) compound 3 is obtained,
Yield about 98.3%.
30.00kg (120.0mol, 1eq) compound 3 is added to 14.40kg (360.0mol, 3eq) sodium hydroxide
150.00kg (5w/w) aqueous solution, 20~30 DEG C of stirrings.After reaction plus 1N dilute hydrochloric acid tune pH to 4, add 30.00kg (1w/
W) ethyl acetate extracts, and organic addition 30.00kg (1w/w) purified water washed once, organic addition 30.00kg (1w/w) saturation
Sodium-chloride water solution washing adds 1.50kg (0.05w/w) anhydrous sodium sulfate dry.40 DEG C of organic phase are concentrated to dryness, and obtain
27.30kg (115.6mol) compound 4, yield about 96.4%.
27.00kg (114.3mol, 1eq) compound 4 is added in 216.00kg (8.0w/w) acetic anhydride, is added
75.60kg (2.8w/w) sodium acetate rises to 90~100 DEG C of reactions, reacts 1~2 hour.Reaction solution is transferred to after reaction
It is stirred 2 hours in 270.00kg (10w/w) purified water, 81.00kg (3w/w) ethyl acetate is added to extract.Organic addition 27.00kg
(1.0w/w) purified water washes twice, and organic addition 27.00kg (1.0w/w) saturated sodium-chloride water solution washing adds 2.70kg
(0.1w/w) anhydrous sodium sulfate is dry.40 DEG C of organic phase are concentrated to dryness.Obtain 14.26kg (81.8mol) compound 5, yield
About 71.6%.1HNMR(400MHz,dDMSO) δ: 0.92~0.96 (t, 3H ,-CH3), 1.37~1.42 (m, 2H ,-CH2CH3),
1.68~1.72 (m, 2H ,-C H2CH2CH3), 2.77~2.81 (t, 2H, Ar-CH2-CH2), 6.59 (s, 1H ,-ArH), 7.20~
7.24 (m, 2H, ArH), 7.49~7.56 (m, 2 H, ArH).13CNMR(400Hz,DMSO)δ:159.76,154.46,129.07,
123.61,122.95,120.72,111.03,102.41,29.71,27.79,22.12,14. 05 sees attached drawing 1~2.
17.00kg (111.7mol, 1eq) compound 6 is added in 34.00kg (2w/w) toluene, 33.31kg is added
(280.0mol, 2.5eq) thionyl chloride is heated to 75~85 DEG C, insulation reaction 2~4 hours.65 DEG C of decompressions after reaction
Divide exactly solvent, obtains 18.99kg (111.3mol) colourless solution compound 7, yield about 97.4%.
10.70kg (80.4mol, 1.0eq) alchlor is added to -20~-10 DEG C of 60.00kg 1, bis- chloroethene of 2-
In alkane, it is added with stirring 14.00kg (80.4mol, 1.0eq) compound 5, after mixing evenly, is added at -20~-10 DEG C
16.46kg (96.5mol, 1.2eq) compound 7, insulation reaction 1~2 hour.Reaction solution is transferred to 90.00kg after reaction
In purified water, pH to 2 is adjusted with dilute hydrochloric acid, the organic addition 45.00kg of liquid separation is purified water washing 2 times, and organic addition 45.00kg is full
It is washed with sodium-chloride water solution, adds 1.40kg anhydrous sodium sulfate dry.55 DEG C of organic phase reduced pressures, obtain 20.11kg
(65.0mol) compound 8.Yield about 81.2%.
20.00kg (64.9mol, 1.0eq) compound 8 is added in 60.00kg (3w/w) toluene, 9.52kg is added
(71.4mol, 1.1eq) alchlor rises to 80~90 DEG C and reacts 2~4 hours.Reaction solution is transferred to after reaction
In 90.00kg (4.5w/w) purified water, pH to 2, organic addition 50.00kg (2.5w/w) purified water of liquid separation are adjusted with dilute hydrochloric acid
Washing 2 times, organic addition 50.00kg (2.5w/w) saturated sodium-chloride water solution washing, adds 2.00kg (0.1w/w) anhydrous slufuric acid
Sodium is dry.65 DEG C of organic phase reduced pressures are cooled to 0 DEG C until there is solid precipitation, keep the temperature crystallization 4 hours.It filters, 80 DEG C of wet product
Under the conditions of be dried in vacuo, obtain off-white color crystalline powder 16.60kg (56.4mol) compound 9, yield about 86.9%.
1HNMR(400MHz,dDMSO) δ: 0.81~0.85 (t, 3H ,-CH3), 1.24~1.29 (m, 2H ,-CH2CH3),1.68
~1.70 (m, 2H ,-C H2CH2CH3), 2.82~2.85 (t, 2H, Ar-CH2-CH2), 6.91~7.72 (m, 8H, ArH), 10.46
(m,1H,-OH).13CNMR(400 Hz,DMSO)δ:189.72,163.49,162.69,153.48,132.08,130.16,
127.28,124.87,123.98,121.16,116.90,11 5.78,111.51,29.94,27.51,22.09,13.84.See
Attached drawing 3~4.
It is operated according to embodiment 1, total recovery 46.6%.
Embodiment 2:
15.00kg (122.8mol, 1eq) compound 1 and 30.82kg (147.4mol, 1.2eq) compound 2 are added to
In 120.00kg (8w/w) ethyl acetate, addition 10.19kg (73.7mol, 0.6eq) potassium carbonate, 1.00kg (2.5mol,
0.02eq) methyl tricapryl ammonium chloride stirs and is warming up to 75~85 DEG C, reaction 1~2 hour.It filters after reaction, filtrate
60.00kg (4w/w) purified water is added to wash, 40 DEG C of organic phase are concentrated to dryness.26.21kg (104.7mol) compound 3 is obtained,
Yield about 85.3%.
26.00kg (103.9mol, 1eq) compound 3 is added to 12.47kg (311.7mol, 3eq) sodium hydroxide
130.00kg (5w/w) methanol solution, 20~30 DEG C of stirrings.It is concentrated to dryness for 40 DEG C after reaction.Add 130.00kg
(5w/w) aqueous dissolution adds 1N dilute hydrochloric acid tune pH to 4, adds 26.00kg (1w/w) ethyl acetate to extract, organic addition
26.00kg (1w/w) purified water washed once, and organic addition 26.00kg (1w/w) saturated sodium-chloride water solution washing adds
1.30kg (0.05w/w) anhydrous sodium sulfate is dry.40 DEG C of organic phase are concentrated to dryness.Obtain 23.50kg (99.5mol) chemical combination
Object 4, yield about 95.8%.
23.00kg (97.4mol, 1eq) compound 4 is added in 184.00kg (8.0w/w) acetic anhydride, is added
64.40kg (2.8w/w) sodium acetate rises to 90~100 DEG C of reactions, reacts 1~2 hour.Reaction solution is transferred to after reaction
It is stirred 2 hours in 230.00kg (10w/w) purified water, 69.00kg (3w/w) ethyl acetate is added to extract.Organic addition 23.00kg
(1.0w/w) purified water washes twice, and organic addition 23.00kg (1.0w/w) saturated sodium-chloride water solution washing adds 2.30kg
(0.1w/w) anhydrous sodium sulfate is dry.40 DEG C of organic phase are concentrated to dryness.Obtain 12.28kg (70.5mol) compound 5, yield
About 72.4%.
15.00kg (98.6mol, 1eq) compound 6 is added in 30.00kg (2w/w) toluene, 35.20kg is added
(295.8mol, 3eq) thionyl chloride is heated to 75~85 DEG C, insulation reaction 2~4 hours.65 DEG C of decompressions are whole after reaction
Except solvent, 16.63kg (97.5mol) colourless solution compound 7, yield about 98.9% are obtained.
27.56kg (206.7mol, 3.0eq) alchlor is added to -20~-10 DEG C of 60.00kg 1, bis- chloroethene of 2-
In alkane, it is added with stirring 12.00kg (68.9mol, 1.0eq) compound 5, after mixing evenly, is added at -20~-10 DEG C
14.11kg (82.7mol, 1.2eq) compound 7, insulation reaction 1~2 hour.Reaction solution is transferred to 80.00kg after reaction
In purified water, pH to 2 is adjusted with dilute hydrochloric acid, the organic addition 40.00kg of liquid separation is purified water washing 2 times, and organic addition 40.00kg is full
It is washed with sodium-chloride water solution, adds 1.20kg anhydrous sodium sulfate dry.55 DEG C of organic phase reduced pressures, obtain 17.17kg
(55.7mol) compound 8, yield about 80.8%.
17.00kg (55.1mol, 1.0eq) compound 8 is added in 51.00kg (3w/w) toluene, 22.04kg is added
(165.3mol, 3.0eq) alchlor rises to 80~90 DEG C and reacts 2~4 hours.Reaction solution is transferred to after reaction
76.50kg in (4.5w/w) purified water, adjusting pH to 2, liquid separation, organic addition 42.50kg (2.5w/w) purified water with dilute hydrochloric acid
Washing 2 times, organic addition 42.50kg (2.5w/w) saturated sodium-chloride water solution washing, adds 1.70kg (0.1w/w) anhydrous slufuric acid
Sodium is dry.65 DEG C of organic phase reduced pressures are cooled to 0 DEG C until there is solid precipitation, keep the temperature crystallization 4 hours.It filters, 80 DEG C of wet product
Under the conditions of be dried in vacuo, obtain off-white color crystalline powder 13.81kg (46.9mol) compound 9, yield about 85.1%.
It is operated according to embodiment 2, total recovery 40.2%.
Embodiment 3:
15.00kg (122.8mol, 1eq) compound 1 and 30.82kg (147.4mol, 1.2eq) compound 2 are added to
In 120.00kg (8w/w) toluene, 24.00kg (73.7mol, 0.6eq) cesium carbonate, 1.00kg (2.5mol, 0.02eq) is added
Methyl tricapryl ammonium chloride stirs and is warming up to 75~85 DEG C, reaction 1~2 hour.It filters after reaction, filtrate adds
The washing of 60.00kg (4w/w) purified water, 40 DEG C of organic phase are concentrated to dryness.30.36kg (121.3mol) compound 3 is obtained, is received
Rate about 98.8%.
30.00kg (120.0mol, 1eq) compound 3 is added to 20.20kg (360.0mol, 3eq) potassium hydroxide
150.00kg (5w/w) aqueous solution, 20~30 DEG C of stirrings.After reaction plus 1N dilute hydrochloric acid tune pH to 4, add 30.00kg (1w/
W) ethyl acetate extracts, and organic addition 30.00kg (1w/w) purified water washed once, organic addition 30.00kg (1w/w) saturation
Sodium-chloride water solution washing adds 1.50kg (0.05w/w) anhydrous sodium sulfate dry.40 DEG C of organic phase are concentrated to dryness.?
27.11kg (114.7mol) compound 4, yield about 95.6%.
27.00kg (114.3mol, 1eq) compound 4 is added in 432.00kg (16.0w/w) acetic anhydride, is added
75.60kg (2.8w/w) sodium acetate rises to 90~100 DEG C of reactions, reacts 1~2 hour.Reaction solution is transferred to after reaction
It is stirred 5 hours in 540.00kg (20w/w) purified water, 81.00kg (3w/w) ethyl acetate is added to extract.Organic addition 27.00kg
(1.0w/w) purified water washes twice, and organic addition 27.00kg (1.0w/w) saturated sodium-chloride water solution washing adds 2.70kg
(0.1w/w) anhydrous sodium sulfate is dry.40 DEG C of organic phase are concentrated to dryness.Obtain 14.57kg (83.6mol) compound 5, yield
About 73.1%.
17.00kg (111.7mol, 1eq) compound 6 is added in 34.00kg (2w/w) toluene, 35.20kg is added
(295.8mol, 3eq) thionyl chloride is heated to 75~85 DEG C, insulation reaction 2~4 hours.65 DEG C of decompressions are whole after reaction
Except solvent, 19.21kg (112.6mol) colourless solution compound 7, yield about 100.0% are obtained.
10.70kg (80.4mol, 1.0eq) alchlor is added in -20~-10 DEG C of 60.00kg toluene, is stirred
Lower addition 14.00kg (80.4mol, 1.0eq) compound 5, after mixing evenly, is added 16.46kg at -20~-10 DEG C
(96.5mol, 1.2eq) compound 7, insulation reaction 1~2 hour.Reaction solution is transferred to 90.00kg purified water after reaction
In, pH to 2 is adjusted with dilute hydrochloric acid, the organic addition 45.00kg of liquid separation is purified water washing 2 times, and organic addition 45.00kg is saturated chlorination
Sodium water solution washing adds 1.40kg anhydrous sodium sulfate dry.10.72kg (80.4mol, 1.0eq) trichlorine is added into organic phase
Change aluminium, rises to 80~90 DEG C and react 2~4 hours.Reaction solution is transferred in 90.00kg purified water after reaction, uses dilute hydrochloric acid
PH to 2 is adjusted, the organic addition 50.00kg of liquid separation is purified water washing 2 times, and organic addition 50.00kg saturated sodium-chloride water solution is washed
It washs, adds 2.00kg anhydrous sodium sulfate dry.65 DEG C of organic phase reduced pressures are cooled to 0 DEG C until there is solid precipitation, keep the temperature crystallization 4
Hour.It filters, is dried in vacuo under the conditions of 80 DEG C of wet product, obtains off-white color crystalline powder 14.47kg (45.2mol) compound 9, receive
Rate about 61.2%.
It is operated according to embodiment 3, total recovery 42.3%.
Comparative example 1 (CN104262304):
700g (5.7mol, 1.0eq) compound 1 is added in 2000g ethyl acetate, after mixing evenly, starts slowly to add
Enter 1400g (6.7mol, 1.2eq) compound 2, finish, sequentially adds 150g (0.46mol, 0.08eq) cesium carbonate and 50g
Then (0.12mol, 0.02eq) methyl tricapryl ammonium chloride is to slowly warm up to 80 DEG C, insulation reaction 8 hours, reaction terminated to subtract
Pressure boils off ethyl acetate, steamed, and 2500g toluene is added, and temperature control continuously adds 250g (4.6mol, 0.8eq) methanol to 20 DEG C
Sodium is heated to flowing back, and insulation reaction 5 hours；Reaction terminates, and dilute hydrochloric acid is added, and adjusts pH to 7, stands, and divides and goes water phase；Continue
Add 600g water to be extracted twice, discard water phase, organic phase vacuum distillation removes toluene, collects 135 DEG C of fractions.Obtain pale yellow transparent
Liquid 383g (2.2mol) compound 5, yield about 38.6%.
It will be added in 2400g toluene with 360g (2.1mol, 1.0eq) compound 5, and be heated to flowing back, heat preservation dehydration 4 is small
When；Dehydration terminates, and is cooled to 15 DEG C, and 420g (2.5mol, 1.2eq) compound 7,240g (1.8mol, 0.86eq) chlorination is added
Zinc, 60g (0.81mol, 0.4eq) N-Nitrosodimethylamine, are to slowly warm up to 80 DEG C, insulation reaction 10 hours；Reaction terminates, and adds
Enter dilute hydrochloric acid, being adjusted to pH is 1~2, is continued insulated and stirred 2 hours, stands, discards water phase；Continue plus water 450g is extracted twice, abandons
Water phase is gone, organic phase is heated to flowing back, heat preservation dehydration 4 hours；Dehydration terminates, and is cooled to 10 DEG C, be added 270g (2.1mol,
1eq) alchlor is to slowly warm up to 75 DEG C, insulation reaction 8 hours；Reaction terminates, and saturated sodium bicarbonate aqueous solution is added, and adjusts
It is 7 to pH, stands, discard water phase；Add the extraction of 360g saturated salt solution three times, discard water phase, organic phase vacuum distillation is steamed to having
Solid is precipitated, and is down to 0 DEG C, insulated and stirred 4 hours.It filters, wet product is dried in vacuo 8 hours under the conditions of 80 DEG C, obtains off-white color knot
Crystalline substance powder 323g (1.1mol, 1eq) compound 9, yield about 52.4%.
It is operated according to comparative example 1, total recovery 20.2%.
Comparative example 2 (CN107382925):
610g (5.0mol, 1.0eq) compound 1 and 1728g (12.5mol, 2.5eq) potassium carbonate are added to 610kg
In the mixed liquor of (1w/w) DMF and 1830kg (3w/w) toluene, it is warming up to 60~70 DEG C of heat preservation half an hour under stirring, is warming up to
80~100 DEG C of heat preservations are added dropwise, and 1098g (5.3mol, 1.05eq) compound 2 reacts 2 hours.After reaction plus 1830g is washed
It washs twice, 80 DEG C of organic phase are concentrated to dryness.Obtain 1126g (121.3mol) compound 3, yield about 90.1%.
By 1100g (4.4mol, 1.0eq) compound 3 be added to 514g (4.8mol, 1.1eq) trimethyl orthoformate and
In 11kg (10w/w) methanol solution of 7.6g (47mmol, 0.01eq) p-methyl benzenesulfonic acid, 20~30 DEG C are stirred 3 hours, are added
2.4g (44mmol, 0.01eq) is stirred 1 hour.It is concentrated to dryness for 40 DEG C later.1170g (3.9mol) compound 0 is obtained, is received
Rate about 89.7%.
1100g (3.7mol, 1eq) compound 0 is added in 2200g (2w/w) toluene, 163g is added with stirring
The solution that (4.1mol, 1.1eq) sodium hydroxide and 2200g (2w/w) water are made into, 35~40 DEG C of stirrings keep the temperature 4 hours.Reaction knot
Beam adds 110g (0.1w/w) sodium chloride, and hydrochloric acid tune pH value 1~2 is added dropwise.Liquid separation obtains the toluene organic phase containing compound 4.Xiang You
Machine is added to 415g (4.1mol, 1.1eq) triethylamine, rises to 70~80 DEG C of reactions, and 782g (4.1mol, 1.1eq) is added dropwise to first
Benzene sulfonyl chloride, drop finish 70~80 DEG C insulation reaction 2 hours, and 164g (4.1mol, 1.1eq) sodium hydroxide and 2200g (2w/ is added dropwise
W) solution that water is made into, drop finish 70~80 DEG C insulation reaction 2 hours.Liquid separation, organic phase is with 1100g 0.1M salt acid elution into
Property, 80 DEG C of organic phase are concentrated to dryness.Obtain 453g (2.6mol) compound 5, yield about 70.0%.
409g (2.4mol, 1.0eq) compound 7,336g (2.5mol, 1.05eq) alchlor are added to -20~-10
DEG C 60.00kg 1, in 2- dichloroethanes, be added with stirring 418g (2.4mol, 1.0eq) compound 5, insulation reaction 4 hours.
320g (2.4mol, 1.0eq) alchlor is added into organic phase, rises to reflux, back flow reaction 6 hours.After reaction will
Reaction solution is transferred in 1000g purified water, and the organic addition 500g of liquid separation is purified water washing 2 times, and it is white to obtain class for organic phase column chromatographic purifying
Color crystalline powder 283g (1.0mol) compound 9, yield about 40.1%.
It is operated by comparative example 2, total recovery 22.7%.
Claims (10)
1. a kind of preparation method of Amiodarone Hydrochloride intermediate, characterized by comprising:
1) with compound 2 nucleophilic substitution occurs in the presence of a phase transfer catalyst for compound 1 under alkaline condition
Close object 3；
2) compound 3 hydrolyzes under alkaline condition generates compound 4；
3) by intramolecular aldol condensation, decarboxylation is dehydrated to obtain compound 5 compound 4 again；
4) compound 6 is reacted with thionyl chloride heating generates compound 7；
5) compound 5 obtains compound 8 with the generation friedel-crafts acylation reaction of compound 7 in the presence of a lewis acid；
6) demethylation generates compound 9, i.e. Amiodarone Hydrochloride intermediate 2- butyl -3- (4- to compound 8 in the presence of a lewis acid
Hydroxy benzoyl) benzofuran
2. according to the method described in claim 1, it is characterized by: above-mentioned steps 1) described in reaction temperature be 60~100 DEG C；
The reaction dissolvent is polar non-solute or nonpolar solvent；The reaction is inorganic weak bases with alkali；The phase transfer is urged
Agent is quaternary ammonium salt；The base amount is 0.2~1.0 molar equivalent；The phase transfer catalyst dosage is 0.01~0.10
Molar equivalent.
3. according to the method described in claim 2, it is characterized by: above-mentioned steps 1) described in reaction temperature be 60~100 DEG C；
The reaction dissolvent is DMF or ethyl acetate；The reaction is potassium carbonate, sodium carbonate or cesium carbonate with alkali；The phase transfer is urged
Agent is methyl tricapryl ammonium chloride.
4. according to the method described in claim 1, it is characterized by: above-mentioned steps 2) described in reaction temperature be 20~30 DEG C；
The reaction dissolvent is protonic solvent；Reaction alkali is inorganic middle highly basic；The base amount is 1~4 molar equivalent.
5. according to the method described in claim 4, it is characterized by: the reaction dissolvent is water, methanol or ethyl alcohol；It is described anti-
It is sodium hydroxide, potassium hydroxide or lithium hydroxide using alkali.
6. according to the method described in claim 1, it is characterized by: above-mentioned steps 3) described in reaction temperature be 90~100 DEG C；
The dehydrating agent be acetic anhydride, the dehydrating agent dosage be 2~8w/w, the inorganic weak bases be sodium acetate, dosage 2~
4w/w。
7. according to the method described in claim 1, it is characterized by: above-mentioned steps 4) described in reaction temperature be 60~100 DEG C；
The reaction dissolvent is polar non-solute or nonpolar solvent, preferably acetonitrile, toluene；The thionyl chloride dosage is 2
~5 molar equivalents.
8. according to the method described in claim 7, it is characterized by: above-mentioned steps 4) described in reaction dissolvent be acetonitrile or first
Benzene.
9. according to the method described in claim 1, it is characterized by: above-mentioned steps 5) described in reaction temperature be -30~0 DEG C；
The lewis acid is alchlor, and the lewis acid dosage is 1~3 molar equivalent.
10. according to the method described in claim 1, it is characterized by: above-mentioned steps 6) described in reaction temperature be 40~80 DEG C；
The solvent is toluene；The preferred alchlor of the lewis acid, the lewis acid dosage are 1~3 mole and work as
Amount.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114671836A (en) * | 2021-12-30 | 2022-06-28 | 南京望知星医药科技有限公司 | Synthesis method of amiodarone impurity C |
| IT202100031259A1 (en) | 2021-12-14 | 2023-06-14 | Cambrex Profarmaco Milano S R L | PROCESS FOR THE PREPARATION OF BENZOPURANS |
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| CN101948454A (en) * | 2010-10-11 | 2011-01-19 | 山东邹平大展新材料有限公司 | Method for preparing 2-butyl-5-nitrobenzofuran |
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
| CN107382925A (en) * | 2017-07-20 | 2017-11-24 | 烟台万润药业有限公司 | A kind of preparation method of Amiodarone Hydrochloride |
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| CN101948454A (en) * | 2010-10-11 | 2011-01-19 | 山东邹平大展新材料有限公司 | Method for preparing 2-butyl-5-nitrobenzofuran |
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| CN107382925A (en) * | 2017-07-20 | 2017-11-24 | 烟台万润药业有限公司 | A kind of preparation method of Amiodarone Hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| IT202100031259A1 (en) | 2021-12-14 | 2023-06-14 | Cambrex Profarmaco Milano S R L | PROCESS FOR THE PREPARATION OF BENZOPURANS |
| WO2023110528A1 (en) | 2021-12-14 | 2023-06-22 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of benzofurans |
| CN114671836A (en) * | 2021-12-30 | 2022-06-28 | 南京望知星医药科技有限公司 | Synthesis method of amiodarone impurity C |
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