CN107382925B - A kind of preparation method of Amiodarone Hydrochloride - Google Patents
A kind of preparation method of Amiodarone Hydrochloride Download PDFInfo
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- CN107382925B CN107382925B CN201710595820.3A CN201710595820A CN107382925B CN 107382925 B CN107382925 B CN 107382925B CN 201710595820 A CN201710595820 A CN 201710595820A CN 107382925 B CN107382925 B CN 107382925B
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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 field of medicaments; more particularly to a kind of preparation method of Amiodarone Hydrochloride; this method is mainly using Benzaldehyde,2-hydroxy and 2- bromo caproic acid Arrcostab as raw material; 2- butyl benzofuran is prepared; using 2- butyl benzofuran as raw material; it is paid gram acylation, demethylation, iodo, etherificate and Amiodarone Hydrochloride is prepared using the method for the present invention at salt; its raw material is cheap and easy to get; simple process; the 2- butyl benzofuran and Amiodarone Hydrochloride of high-purity, high yield can be obtained; at low cost, waste water is few, is suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicaments more particularly to a kind of preparation methods of Amiodarone Hydrochloride.
Background technique
Amiodarone (Amiodarone) also known as amiodarone, first by Belgian Marly nitrogen and chemical products company
Synthesis was applied producing in 1961 in West Germany.It is initially to come out as coronary artery dilator.Singh seventies research discovery
Its electro physiology mechanism of action, Rosenbanm in 1976 take the lead in being applied to antiarrhythmic treatment.Amiodarone Hydrochloride is amine
The hydrochloride of iodine ketone, structural formula are as follows:
Amiodarone toxicity is minimum, and intravenous injection lethal dose is 10 times of therapeutic dose, and lethal oral dose greatly may be used very much
Ignore.Therefore, even if long-term larger dose medication is also safe.Amiodarone is from intestinal absorption, and excretion is very slow, according to
RosenbanmShi report, still has 16-34% to be stranded in vivo after drug withdrawal.The medical instrument has antiarrhythmic effect, after drug withdrawal
It can maintain 10-20 days even up to 30-45 days, such patient just need not repeatedly take daily.
Now, amiodarone (or its hydrochloride CAS-RN:19774-82-4) be one be widely used in treatment and prevention room property
And the third class antiarrhythmic drug of supraventricular arrhythmias, there is direct dilating effect to coronary artery and peripheral vessels；It can
Influence thyroxine metabolism.
In the existing method for preparing Amiodarone Hydrochloride, 2- butyl benzofuran and 2- butyl -3- (3,5- bis- iodo- 4- hydroxyls
Base benzoyl) benzofuran (abbreviation PDIB) is the important intermediate for preparing amiodarone, it is entirely with PDIB in existing method
For raw material, then through step etherificate, salt-forming reaction Amiodarone Hydrochloride can be prepared, reaction equation is as follows:
Therefore, synthetic method summary statement of the emphasis with regard to 2- butyl benzofuran or its analog and PDIB or its analog
It is as follows:
Route 1: using salicylaldhyde and 2- monoxone as raw material (Chinese Journal of Pharmaceuticals, 1980 (2): 1-4)
The method, step is more, complex process, and the raw material environmental pollution of selection is serious, and overall yield of reaction is low, only 20-
25%, synthesis cost is high.
Route 2:2- butyl benzofuran is raw material (US5266711)
Method described in US5266711 using 2- butyl benzofuran, methyl phenyl ethers anisole, phosgene as raw material, be successively substituted reaction,
Amiodarone is prepared in iodide reaction.The essence of " substitution reaction " is first to be prepared with phosgene and methyl phenyl ethers anisole reaction in this method
Anisoyl chloride, under the catalysis of alchlor, anisoyl chloride replaces with 2- butyl benzofuran
It reacts, phosgene, dangerous environmental protection has been used in this method, in addition, market supply is insufficient at home for raw material 2- butyl benzofuran.
Route 3: using 2- hydroxyl -5- bromobenzaldehyde and 2- bromocaproic acid methyl esters as raw material (US8871956)
The route products therefrom is 5- bromo -2- butyl benzofuran；In the route, hydrolysis of ester group in second step reaction
When, cannizzaro's reaction easily occurs, the step yield and product purity are lower, cause entire reaction route yield to reduce, text
Offer yield 52%；In addition, tosylate chloride used, easily hydrolytic spoilage, it must strict control system water content.
Route 4: using salicylaldhyde and 2- bromocaproic acid methyl esters as raw material (CN1858042)
In patent CN1858042, using Benzaldehyde,2-hydroxy, 2- bromocaproic acid methyl esters as raw material successively etherified reaction, cyclization
PDIB is prepared in reaction, F-K reaction, iodide reaction.Route methods preparation gained 2- butyl benzofuran yield
And purity is extremely low.
Beneficial effects of the present invention；The method of the present invention raw material are cheap and easy to get, and simple process, production cost is low, obtain
Amiodarone Hydrochloride yield, purity is high.
Summary of the invention
For it is above-mentioned prepare yield brought by Amiodarone Hydrochloride, purity is low the problems such as, the present invention provides a kind of safety collar
It protects, raw material are cheap and easy to get, and simple process, production cost is low, the preparation method of yield, Amiodarone Hydrochloride with high purity.
The technical scheme to solve the above technical problems is that the present invention provides a kind of preparation side of Amiodarone Hydrochloride
Method, comprising the following steps:
A, under condition of normal pressure, in the in the mixed solvent of polar non-solute and toluene, Benzaldehyde,2-hydroxy and nothing is added
Aqueous carbonate potassium reacts 0.5h under the conditions of 60-70 DEG C of temperature, then 80-100 DEG C at a temperature of, 2- bromo caproic acid Arrcostab is added dropwise
It is stirred to react 2h, layering obtains organic phase, steams solvent and obtain compound shown in the formula 3；
B, compound shown in formula 3 that step A is obtained is dissolved in methanol, trimethyl orthoformate is then added, to toluene sulphur
Acid is stirred to react 3 hours under the conditions of 20-30 DEG C, adds sodium methoxide and be stirred to react 1h, steam solvent, obtains 4 institute of formula
Show compound；
C, compound shown in formula 4 that step B is obtained is dissolved in toluene, sodium hydroxide is added and is stirred under the conditions of 30-40 DEG C
Reaction 4 hours is mixed, sodium chloride is then added, then salt acid for adjusting pH is added dropwise to 1-2, separates organic layer, obtain 5 shownization of formula
Close object；
D, compound shown in the formula 5 for obtaining step C is added in triethylamine, is warming up to 70-80 DEG C, and tolysulfonyl is added
The toluene solution of chlorine 70-80 DEG C insulation reaction 2 hours, add sodium hydroxide, 70-75 DEG C keep the temperature 2 hours, stand, point
Layer, separates organic phase, and dilute hydrochloric acid is washed to neutrality, steams solvent and obtains intermediate 2- butyl benzofuran crude product shown in formula 2,
The fine work of 2- butyl benzofuran, structure shown in depicted 2 are obtained through vacuum distillation；
E, under the conditions of -20 DEG C to -15 DEG C, into the mixture of anisoyl chloride, alchlor and halogenated hydrocarbons,
It is added dropwise to intermediate 2- butyl benzofuran fine work shown in formula 2 obtained in step D, insulation reaction 1-8 hours, adds three
Aluminium chloride is flowed back, is quenched, and 6 compound represented of formula is obtained；
F, 6 compound represented of formula obtained in step E is mixed with iodine, low-carbon alcohols, water and potassium carbonate, at 40-65 DEG C
Sodium sulfite quenching reaction is added in reaction 8-10 hours, and regulation system is acidity, and suction filtration obtains 7 compound represented of formula；
G, by 7 compound represented of formula obtained in step F and the chloro- N of 2-, N- diethylethanamine hydrochloride, potassium carbonate, water
It being uniformly mixed with toluene, is stirred to react 4h, stood, organic phase is washed in layering, and adjusting organic phase pH with hydrochloric acid is 1-2 ,-
Solvent is steamed under the conditions of 0.09 to -0.08MPa/40-65 DEG C, obtains the Amiodarone Hydrochloride crude product such as formula 1；
H, it by Amiodarone Hydrochloride crude product obtained in step G, is dissolved in the mixed liquor of methylene chloride and methanol, crosses silica gel
Column is beaten through acetone reflux and refines, obtains Amiodarone Hydrochloride fine work.
As it is of the invention further preferably, in step, the polar non-solute be n,N-Dimethylformamide,
The mixture of one or both of Isosorbide-5-Nitrae-dioxane, the 2- bromo caproic acid Arrcostab are 2- bromo methyl caproate or 2- bromine
For ethyl hexanoate, the molar ratio of the Benzaldehyde,2-hydroxy and the Anhydrous potassium carbonate is 1:(2.5-3.5)；The 2- hydroxy benzenes
The molar ratio of formaldehyde and 2- bromocaproic acid Arrcostab is 1:(1.05-1.5), the Benzaldehyde,2-hydroxy and polar non-solute,
The mass ratio of toluene is 1:(1-1.5): (2-5).
As it is of the invention further preferably, in stepb, compound shown in the formula 3 and trimethyl orthoformate, to toluene
The molar ratio of sulfonic acid and sodium methoxide is 1:(1.1-2.0): (0.01-0.05): (0.01-0.05).
Further preferably as the present invention, in step C, the molar ratio of formula 4 compound represented and sodium hydroxide
For 1:(1.1-1.5)；The sodium chloride and the mass ratio of 4 compound represented of formula are (0.1-0.4): 1.
Further preferably as the present invention, in step D, compound shown in the formula 5 and triethylamine, paratoluensulfonyl chloride
And the molar ratio of sodium hydroxide is 1:(1-1.1): (1-1.1): (1-1.1).
Further preferably as the present invention, in step E, the halogenated hydrocarbons is one of 1,2- dichloroethanes, chlorobenzene
Or two kinds of mixture, the 2- butyl benzofuran and anisoyl chloride, alchlor, the tri-chlorination being added again
The molar ratio of aluminium is 1:(1-1.1): (1-1.2): the mass ratio of (1-1.1), the halogenated hydrocarbons and 2- butyl benzofuran is (2-
6): 1.
Further preferably as the present invention, in step F, the low-carbon alcohols are methanol, in ethyl alcohol, normal propyl alcohol, isopropanol
One or more of mixtures, the molar ratio of 6 compound represented of formula and iodine, potassium carbonate and sodium sulfite is 1:(2-
2.5):(1-1.3):(0.1-0.7)；The mass ratio of the low-carbon alcohols and water, 6 compound represented of formula is (1-5): (1-3): 1.
Further preferably as the present invention, in step G, 7 compound represented of formula and the chloro- N of 2-, N- diethyl second
Amine hydrochlorate, potassium carbonate molar ratio be 1:(1.03-1.1): (2.5-3.5), 7 compound represented of formula and water, toluene
Mass ratio be 1:(1.3-2): (3-4.5).
Further preferably as the present invention, in steph, the Amiodarone Hydrochloride crude product and methylene chloride, methanol, silicon
Glue, acetone mass ratio be 1:(5-20): (0-5): (1-20): (10-15).
It to sum up analyzes, it is cheap and easy to get that this patent method can provide a kind of safety and environmental protection, raw material, simple process, production
It is at low cost, obtained Amiodarone Hydrochloride yield, purity is high.
Specific embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
The synthesis of 1 Amiodarone Hydrochloride of embodiment
A, the synthesis of compound shown in formula 3
276.7g (2.0mol) Anhydrous potassium carbonate, 97.6g (0.8mol) Benzaldehyde,2-hydroxy, 100g are added in 2L there-necked flask
N,N-Dimethylformamide, 300g toluene, mechanical stirring at a temperature of 60-70 DEG C, are reacted 0.5 hour, 80-100 DEG C of temperature
Lower dropwise addition 176.0g (0.84mol) 2- bromo caproic acid Arrcostab, is stirred to react 2 hours, and 320g water is added, and branch vibration layer is organic
Layer is washed once with 320g, and 0.09MPa/80 DEG C is evaporated off solvent, obtains compound 190.2g shown in formula 3, and GC purity 98.8% is received
Rate 95.0% (in terms of Benzaldehyde,2-hydroxy).
B, the synthesis of compound shown in formula 4
Compound 200.4g (0.8mol) shown in formula 3 is added dissolved with 93.4g (0.88mol) trimethyl orthoformate and
In the 2L methanol solution of 1.52g (8mmol) p-methyl benzenesulfonic acid, 20-30 DEG C is stirred 3 hours, and 0.43g (8mmol) sodium methoxide is added,
Stirring steamed solvent after 1 hour, obtained compound 220.5g shown in pale yellow oily liquid formula 4, yield 96.0%, GC purity
98.5%.
C, the synthesis of compound shown in formula 5
In 2L there-necked flask plus 237.1g (0.8mol) compound 4,556.0g toluene, 35.2g (0.88mol) sodium hydroxide with
The solution that 530g water is made into, 35-40 DEG C after insulation reaction 4 hours, is added 23.7g sodium chloride, and concentrated hydrochloric acid, regulation system pH is added dropwise
=1-2, stands, and liquid separation takes organic phase, obtains the toluene solution of compound shown in formula 5, sampling and testing GC purity 98.3%, this is molten
Liquid is directly used in the next step, no yield data.
D, the synthesis of 2- butyl benzofuran
44.5g (0.44mol) three is added in toluene solution (the 5 compound 0.4mol containing formula) containing compound shown in formula 5
Ethamine is warming up to 70-80 DEG C, and the toluene solution of 83.9g (0.44mol) paratoluensulfonyl chloride is added dropwise, and drop finishes, 70-80 DEG C of heat preservation
The aqueous solution of 17.6g (0.44mol) sodium hydroxide is added dropwise in reaction 2 hours, and 70-75 DEG C keeps the temperature 2 hours, stands, and layering separates
Organic phase, dilute hydrochloric acid are washed to neutrality, steam solvent and obtain intermediate 2- butyl benzofuran crude product 72.3g shown in formula 2, warp
Vacuum distillation obtains the fine work 61.7g of 2- butyl benzofuran, is light yellow oil, yield 88.5% is (with chemical combination shown in formula 5
Object meter), GC purity 99.4%.
E, the synthesis of compound shown in formula 6
At -20 to -15 DEG C, in 102.4g (0.6mol) anisoyl chloride, 83.1g (0.631mol) alchlor
And in the mixed liquor of 210g dichloroethanes, it is added dropwise to 104.4g (0.6mol) 2- butyl benzofuran, -20 to -15 DEG C of heat preservations 4 are small
When, 79.1g (0.6mol) alchlor is added, is to slowly warm up to flow back, back flow reaction 6 hours, is added in purified water and is quenched instead
It answers, organic phase is washed to neutrality, crosses silicagel column, in 70-80 DEG C, solvent is evaporated off in -0.085MPa, obtains compound shown in formula 6
162.5g is light yellow solid, yield 92.0% (2- butyl benzofuran meter), GC purity 99.2%.
F, the synthesis of compound shown in formula 7
By compound shown in 100.0g (0.3397mol) formula 6 and 172.5g (0.6796mol) elemental iodine, 100g methanol,
100g water, 47.0g (0.3397mol) potassium carbonate mixing, 40-65 DEG C reaction 8-10 hours, addition 4.3g (0.0340mol) sulfurous
Acid sodium aqueous solution quenching reaction, it is 5-6 that hydrochloric acid, which is adjusted to system pH, 20-30 DEG C, keeps the temperature 2 hours, filters, obtain 7 shownization of formula
Close object, in 70-75 DEG C dry 6 hours, obtain compound 168.2g shown in formula 7, be faint yellow solid powder, yield 90.7% (with
6 compound meter of formula), GC purity 98.1%.
G, prepared by Amiodarone Hydrochloride
Compound shown in 130.0g (0.238mol) formula 7 and 42.2g (0.2452mol) 2- chloro- N, N- diethyl ethanamine salt
Hydrochlorate, 82.2g (0.595mol) potassium carbonate, 170g water and 390g toluene mix, mechanical stirring, and heating reaction 4 hours is stood,
Layering is washed organic phase 2 times, adjusts organic phase pH to 1-2 with hydrochloric acid, -0.09 to -0.08MPa/40-65 DEG C steams solvent, obtains
To Amiodarone Hydrochloride crude product 162.3g shown in formula 1, yield 99.9% (in terms of compound shown in formula 7).
Take 50g Amiodarone Hydrochloride crude product, be dissolved in 100g methylene chloride, cross silica gel (200g) column, with 450g methylene chloride and
The mixed liquor that 70g methanol is made into rushes column, the efflux of hydrochloric amiodarone, and solvent evaporated obtains Amiodarone Hydrochloride a refined product
45g is beaten purification drying through 450g acetone reflux, obtains 43.0g Amiodarone Hydrochloride, refine yield 86%.
Amiodarone Hydrochloride is tested through UV, IR, while carrying out HPLC-MS characterization: found (m/z) M++ 1=646.46, M--1
=644.07 Amiodarone Hydrochloride molecular formula C25H29I2NO3, calculated molecular weight is 645.31；
1HNMR(CDCl3-d1)δ0.909-0.946(3H,t),1.537-1.574(6H,t),1.368-1.387(2H,
m),1.745-1.821(2H,m),3.448-3.484(4H,m),2.867-2.905(2H,t),4.544-4.567(2H,t),
3.695-3.728(2H,q),8.227(2H,s),7.254-7.515(4H)；
13CNMR(CDCl3-d1)δ9.2,13.8,22.5,28.2,30.0,47.9,50.3,67.1,90.6,111.2,
115.6,120.9,124.0,124.8,126.2,139.2,140.8,153.7,160.1,166.7,187.4。
Its quality meets Japanese Pharmacopoeia quality requirement, and test result is as follows shown in table 1:
Table 1
The synthesis of 2 Amiodarone Hydrochloride of embodiment
A, the synthesis of compound shown in formula 3
332.0g (2.4mol) Anhydrous potassium carbonate, 97.6g (0.8mol) Benzaldehyde,2-hydroxy, 130g are added in 2L there-necked flask
N,N-Dimethylformamide, 600g toluene, mechanical stirring at a temperature of 60-70 DEG C, are reacted 0.5 hour, 80-100 DEG C of temperature
Lower dropwise addition 176.0g (0.84mol) 2- bromo caproic acid Arrcostab, is stirred to react 2 hours, and 400g water is added, and branch vibration layer is organic
Layer is washed once with 400g, and solvent is evaporated off in 0.09MPa/80, obtains compound 197.2g shown in formula 3, GC purity 98.6%, yield
98.5% (in terms of Benzaldehyde,2-hydroxy).
B, the synthesis of 4 compound of formula
Compound 200.4g (0.8mol) shown in formula 3 is added dissolved with 127.2g (1.2mol) trimethyl orthoformate and
In the 2L methanol solution of 4.56g (24mmol) p-methyl benzenesulfonic acid, 20-30 DEG C is stirred 3 hours, and 1.29g (24mmol) methanol is added
Sodium, stirring steam solvent after 1 hour, obtain pale yellow oily liquid 227.6g, yield 96.0%, GC purity 98.6%.
C, the synthesis of compound shown in formula 5
Add compound, 556.0g toluene, 41.6g (1.04mol) hydrogen-oxygen shown in 237.1g (0.8mol) formula 4 in 2L there-necked flask
Change the solution that sodium and 530g water are made into, 35-40 DEG C, insulation reaction is added 59.3g sodium chloride, dense salt is added dropwise after reaction 4 hours
Sour concentrated hydrochloric acid, regulation system pH=1-2 are stood, and liquid separation takes organic phase, obtain the toluene solution of compound shown in formula 5, and sampling is surveyed
GC purity 98.6% is tried, this solution is directly used in the next step, no yield data.
D, the synthesis of 2- butyl benzofuran
42.5g (0.42mol) triethylamine is added in the toluene solution (the 5 compound 0.4mol containing formula) of compound shown in formula 5, rises
The toluene solution of 80.1g (0.42mol) paratoluensulfonyl chloride is added dropwise to 70-80 DEG C in temperature, and drop finishes, and 70-80 DEG C of insulation reaction 2 is small
When, the aqueous solution of 16.8g (0.42mol) sodium hydroxide is added dropwise, 70-75 DEG C keeps the temperature 2 hours, stands, and layering separates organic phase,
Dilute hydrochloric acid is washed to neutrality, steams solvent and obtains the intermediate 2- butyl benzofuran crude product 69.7g of structural formula 2, steams through decompression
Evaporate to obtain the fine work 62.7g of 2- butyl benzofuran, be light yellow oil, yield 90.0% (in terms of compound shown in formula 5),
GC purity 99.1%.
E, the synthesis of compound shown in formula 6
At -20 to -15 DEG C, in 107.5g (0.63mol) anisoyl chloride, 87.0g (0.66mol) alchlor
And in the mixed liquor of 417.6g dichloroethanes, it is added dropwise to 104.4g (0.6mol) 2- butyl benzofuran, -20 to -15 DEG C of heat preservations 4
Hour, 83.1g (0.63mol) alchlor is added, is to slowly warm up to flow back, back flow reaction 6 hours, is added in purified water and is quenched
Reaction, organic phase are washed to neutrality, cross silicagel column, in 70-80 DEG C, solvent is evaporated off in -0.085MPa, obtains compound shown in formula 6
163.8g is light yellow solid, yield 92.8% (2- butyl benzofuran meter), GC purity 99.5%.
F, the synthesis of compound shown in formula 7
By compound shown in 100.0g (0.3397mol) formula 6 and 189.7g (0.7473mol) elemental iodine, 300g methanol,
200g water, 51.6g (0.3737mol) potassium carbonate mixing, 40-65 DEG C reaction 8-10 hour, addition 12.8g (0.1019mol) Asia
Aqueous sodium persulfate solution quenching reaction, it is 3-4 that hydrochloric acid, which is adjusted to system pH, 20-30 DEG C, keeps the temperature 2 hours, filters, obtain such as 7 institute of formula
Show compound, dried 6 hours in 70-75 DEG C, obtain 7 compound 176.2g of formula, is faint yellow solid powder, yield 95% is (with formula 6
Compound meter), GC purity 98.9%.
G, prepared by Amiodarone Hydrochloride
Compound shown in 130.0g (0.238mol) formula 7 and 43.4g (0.2523mol) 2- chloro- N, N- diethyl ethanamine salt
Hydrochlorate, 98.9g (0.7164mol) potassium carbonate, 208g water and 495g toluene mix, mechanical stirring, and heating reaction 4 hours is stood,
Layering is washed organic phase 2 times, adjusts organic phase pH to 1-2 with hydrochloric acid, -0.09 to -0.08MPa/40-65 DEG C steams solvent, obtains
To the Amiodarone Hydrochloride crude product 162.4g of such as formula 1, yield 100% (in terms of compound shown in formula 7).
Take 50g Amiodarone Hydrochloride crude product, be dissolved in 100g methylene chloride, cross silica gel (400g) column, with 450g methylene chloride and
The mixed liquor that 70g methanol is made into rushes column, the efflux of hydrochloric amiodarone, and solvent evaporated obtains Amiodarone Hydrochloride a refined product
45g is beaten purification drying through 450g acetone reflux, obtains 43.8g Amiodarone Hydrochloride, refine yield 87.6%.
Amiodarone Hydrochloride is tested through UV, IR, while carrying out HPLC-MS characterization: found (m/z) M++ 1=646.43, M--1
=644.05 Amiodarone Hydrochloride molecular formula C25H29I2NO3, calculated molecular weight is 645.30；
1HNMR(CDCl3-d1)δ0.908-0.945(3H,t),1.536-1.573(6H,t),1.367-1.388(2H,
m),1.744-1.820(2H,m),3.446-3.483(4H,m),2.865-2.903(2H,t),4.542-4.566(2H,t),
3.694-3.726(2H,q),8.226(2H,s),7.253-7.513(4H)；
13CNMR(CDCl3-d1)δ9.1,13.8,22.4,28.1,30.1,47.8,50.4,67.2,90.5,111.2,
115.4,120.9,124.0,124.7,126.2,139.2,140.6,153.5,160.1,166.4,187.3。
Its quality meets Japanese Pharmacopoeia quality requirement, and test result is as follows shown in table 2:
Table 2
The synthesis of 3 Amiodarone Hydrochloride of embodiment
A, the synthesis of compound shown in formula 3
387.3g (2.8mol) Anhydrous potassium carbonate, 97.6g (0.8mol) Benzaldehyde,2-hydroxy, 140g are added in 2L there-necked flask
N,N-Dimethylformamide, 600g toluene, mechanical stirring at a temperature of 60-70 DEG C, are reacted 0.5 hour, 80-100 DEG C of temperature
Lower dropwise addition 176.0g (0.84mol) 2- bromo caproic acid Arrcostab, is stirred to react 2 hours, and 500g water is added, and branch vibration layer is organic
Layer is washed once with 500g, and solvent is evaporated off in 0.09MPa/80, obtains 3 intermediate 198.2g, GC purity 98.9% of formula, yield
99.0% (in terms of Benzaldehyde,2-hydroxy).
B, the synthesis of compound shown in formula 4
Compound 200.4g (0.8mol) shown in formula 3 is added dissolved with 169.8g (1.6mol) trimethyl orthoformate and 7.6g
In the 2L methanol solution of (40mmol) p-methyl benzenesulfonic acid, 20-30 DEG C is stirred 3 hours, and 2.15g (40mmol) sodium methoxide is added, stirs
Solvent is steamed after mixing 1 hour, obtains pale yellow oily liquid 218.1g, yield 92.0%, GC purity 98.2%.
C, the synthesis of compound shown in formula 5
Add compound, 556.0g toluene, 46.4g (1.16mol) hydrogen-oxygen shown in 237.1g (0.8mol) formula 4 in 2L there-necked flask
Change the solution that sodium and 530g water are made into, 35-40 DEG C, sodium chloride is added after reaction 4 hours in insulation reaction, and the dense salt of concentrated hydrochloric acid is added dropwise
Acid, regulation system pH=1-2 are stood, and liquid separation takes organic phase, obtains the toluene solution of compound shown in formula 5, and sampling and testing GC is pure
Degree 98.3%, this solution is directly used in the next step, no yield data.
D, the synthesis of 2- butyl benzofuran
40.5g (0.4mol) three second is added in the toluene solution (containing compound 0.4mol shown in formula 5) of compound shown in formula 5
Amine is warming up to 70-80 DEG C, and the toluene solution of 76.3g (0.4mol) paratoluensulfonyl chloride is added dropwise, and drop finishes, 70-80 DEG C of insulation reaction
2 hours, the aqueous solution of 27.7g sodium hydroxide is added dropwise, 70-75 DEG C keeps the temperature 2 hours, stands, and layering separates organic phase, dilute hydrochloric acid
It is washed to neutrality, solvent is steamed and obtains the intermediate 2- butyl benzofuran crude product 69.5g of structural formula 2, is obtained through vacuum distillation
The fine work 60.7g of 2- butyl benzofuran is light yellow oil, and yield 87.0% (in terms of compound 5 shown in formula 5), GC is pure
Degree 99.3%.
E, the synthesis of compound shown in formula 6
Under the conditions of -20 to -15 DEG C, in 112.6g (0.66mol) anisoyl chloride, 95.0g (0.72mol) trichlorine
In the mixed liquor for changing aluminium and 626g dichloroethanes, it is added dropwise to 104.4g (0.6mol) 2- butyl benzofuran, -20 to -15 DEG C of guarantors
Temperature 4 hours, adds 87.0g (0.66mol) alchlor, is to slowly warm up to flow back, and back flow reaction 6 hours, is added in purified water
Quenching reaction, organic phase are washed to neutrality, cross silicagel column, in 70-80 DEG C, solvent is evaporated off in -0.085MPa, obtains 6 shownization of formula
Object 154.5g is closed, is light yellow solid, yield 87.5% (2- butyl benzofuran meter), GC purity 99.0%.
F, the synthesis of compound shown in formula 7
By compound shown in 100.0g (0.3397mol) formula 6 and 215.6g (0.8493mol) elemental iodine, 500g methanol,
300g water, 61.0g (0.4416mol) potassium carbonate mixing, 40-65 DEG C reaction 8-10 hour, addition 30.0g (0.2378mol) Asia
Aqueous sodium persulfate solution quenching reaction, it is 1-2 that hydrochloric acid, which is adjusted to system pH, 20-30 DEG C, keeps the temperature 2 hours, filters, obtain such as 7 institute of formula
Show compound, dried 6 hours in 70-75 DEG C, obtain compound 183.2g shown in formula 7, is faint yellow solid powder, yield 98.8%
(in terms of compound shown in formula 6), GC purity 99.6%.
G, prepared by Amiodarone Hydrochloride
Compound shown in 130.0g (0.238mol) formula 7 and 45.1g (0.2618mol) 2- chloro- N, N- diethyl ethanamine salt
Hydrochlorate, 115.1g (0.833mol) potassium carbonate, 260g water and 585g toluene mix, mechanical stirring, and heating reaction 4 hours is stood,
Layering is washed organic phase 2 times, adjusts organic phase pH to 1-2 with hydrochloric acid, -0.09 to -0.08MPa/40-65 DEG C steams solvent, obtains
To Amiodarone Hydrochloride crude product 162.0g as shown in Equation 1, yield 99.8% (in terms of 7 compound of formula).
50g Amiodarone Hydrochloride crude product is dissolved in 100g methylene chloride, silica gel (600g) column is crossed, with 450g methylene chloride and 70g
The mixed liquor that methanol is made into rushes column, the efflux of hydrochloric amiodarone, and solvent evaporated obtains Amiodarone Hydrochloride a refined product 45g,
It is beaten purification drying through 450g acetone reflux, 43.5g Amiodarone Hydrochloride is obtained, refines yield 87%.
Amiodarone Hydrochloride is tested through UV, IR, while carrying out HPLC-MS characterization: found (m/z) M++ 1=646.47, M--1
=644.08 Amiodarone Hydrochloride molecular formula C25H29I2NO3, calculated molecular weight is 645.33；
1HNMR(CDCl3-d1)δ0.911-0.947(3H,t),1.538-1.575(6H,t),1.369-1.388(2H,
m),1.747-1.820(2H,m),3.446-3.483(4H,m),2.864-2.901(2H,t),4.543-4.567(2H,t),
3.695-3.726(2H,q),8.227(2H,s),7.254-7.515(4H)；
13CNMR(CDCl3-d1)δ9.2,13.5,22.5,28.2,30.0,47.6,50.3,67.2,90.6,111.2,
115.4,120.9,124.0,124.8,126.1,139.2,140.8,153.7,160.1,166.6,187.4。
Its quality meets Japanese Pharmacopoeia quality requirement, and test result is as follows shown in table 3:
Table 3
Comparative test:
1, in the embodiment of the present invention 1 preparation method of the compound shown in formula 5 and Publication No. US8871956 patent
Preparation method, purity, the yield contrast and experiment of the compound shown in formula 5 are as shown in table 4 below:
Table 4
In the Publication No. US8871956 patent, compound shown in preparation formula 5, step is the following steps are included: formula 3
Compound is dissolved in methyl tertiary butyl ether(MTBE), 20 DEG C, sodium hydrate aqueous solution is added, is warming up to 40 DEG C of reactions, reaction terminates, concentrated hydrochloric acid
For regulation system to highly acid, liquid separation obtains the solution of compound shown in formula 5.
Compound shown in 1 Chinese style 3 of the embodiment of the present invention becomes compound shown in formula 4 through acetalation, continues alkali
Property under the conditions of hydrolysis of ester group reaction, avoid Kang Nizhaluo side reaction in Publication No. US8871956 patent, the product of formula 5
Purity and yield significantly improve, almost quantitative reaction, the analysis of causes: the aromatic aldehyde without α-H, in the work of sodium hydrate aqueous solution
Under, cannizzaro's reaction easily occurs, by the aromatic aldehyde of no α-H after acetalation is protected, it is anti-that Ni Zhaluo no longer occurs for aldehyde radical
It answers, causes to react purity and yield significantly improves.
2, the 2- butyl benzofuran and the patent system of Publication No. CN1858042 that the embodiment of the present invention 1 is prepared are standby
2- butyl benzofuran, contrast and experiment are as shown in table 5 below:
Table 5
In CN1858042 patent, preparing 2- butyl benzofuran, steps are as follows: the toluene of compound shown in formula 3 is molten
Liquid steams solvent, obtains raffinate, and propyl alcohol, sodium hydroxide, back flow reaction is added, and reaction terminates, steams solvent, add toluene and water,
Acidification, reflux water-dividing obtain the toluene solution of 2- butyl benzofuran.
Using Benzaldehyde,2-hydroxy and 2- bromo caproic acid Arrcostab as raw material in the embodiment of the present invention 1, successively through changing shown in formula 3
Compound shown in object, formula 4, compound shown in formula 5 are closed, final transformation obtains 2- butyl benzofuran, the reaction of this 4 step, Ke Yiyu
It is completed in " one pot ", it is intermediate without purification operations, only in four steps, simple vacuum distillation purification is carried out, it is pure GC can be obtained
The 2- butyl benzofuran of 99.0% or more degree, 4 step overall yield of reaction 84-88% (in terms of Benzaldehyde,2-hydroxy).With reference to this hair
Bright method and the method for CN1858042 compare experiment, prepare 2- butyl benzofuran, the method for the present invention preparation gained 2- fourth
Base benzofuran purity and yield are higher.
The reason of leading to 2- butyl benzofuran GC purity, total recovery difference in table 5 analysis: mixed acid anhydride of the invention
Ester group cyclization of the activity than CN1858042 of cyclization is high, and raw material is easier to be converted to target product 2- butyl benzofuran, so
The method of the present invention purity and yield are higher.
In addition, the method for the present invention is not with allowing the paratoluensulfonyl chloride of facile hydrolysis to substitute easily hydrolyzing in US8871956
Benzene sulfonyl chloride, improving reaction system reduces the dosage of acyl chlorides to the tolerance of water, and then reduces corresponding triethylamine and hydrogen
The dosage of sodium oxide molybdena reduces wastewater treatment difficulty and wastewater flow rate, makes so that the COD value and salinity of corresponding waste water are decreased obviously
Technique is more environmentally-friendly.
3, the patent of the embodiment of the present invention 1 and Publication No. US5266711, the successive addition about 2- butyl benzofuran
(2- butyl benzofuran is incorporated as " rear adding manner " to mode after other all materials in the reaction；2- fourth in the reaction
Base benzofuran is incorporated as " first adding manner " before other any materials；), the comparison of compound shown in obtained formula 6
Experimental result is as shown in table 6 below:
Table 6
Its step of specific method in US5266711 patent: -20 DEG C, phosgene, 2- butyl benzofuran, alchlor add
Enter methyl phenyl ethers anisole, temperature reaction, compound shown in preparation formula 6.
The feed way of 2- butyl benzofuran, reaction gained 6 shownization of formula are added after taking in the embodiment of the present invention 1
The purity and yield for closing object significantly improve, and the feed way of 2- butyl benzofuran is first added in patent US5266711, generate
More impurity, product yield are low.
4, the patent of the embodiment of the present invention 1 and Publication No. CN1858042, the preparation comparative experiments about 7 compound of formula
As a result as shown in table 7 below:
Table 7
In CN1858042 patent, the specific steps are that: by 2- butyl -3- (4- hydroxy benzoyl) benzofuran with
Iodine carries out back flow reaction under the action of oxidant and acid binding agent in solvent, and solvent is the aliphatic alcohols solvent of Cl-6, institute
Obtaining product is 2- butyl -3- (4- hydroxyl -3,5- diiodo-benzene formyl benzofuran), and oxidant is hydrogen peroxide.
When the preparation of compound shown in formula 7, compared with being prepared in CN1858042 patent, hydrogen peroxide is not used, reduces miscellaneous
The generation of matter, while reaction temperature is reduced, reduce the loss of elemental iodine, makes a more iodo intermediate conversion accepted way of doing sth 7
Shown compound, compound purity shown in gained formula 7 significantly improve.
Table 8 is that Amiodarone Hydrochloride is as follows in Japanese Pharmacopoeia quality requirement specific targets:
Table 8
Its " related substances 1 " are the chloro- N of 2- in table 1, table 2, table 3, table 8, and N- diethyl ethanamine, " related substances 2 " are salt
The translated next expression way of sour amiodarone Japanese Pharmacopoeia, does not imply that a specific substance.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Amiodarone Hydrochloride, which comprises the following steps:
A, under condition of normal pressure, in the in the mixed solvent of polar non-solute and toluene, Benzaldehyde,2-hydroxy and anhydrous carbon is added
Sour potassium reacts 0.5h under the conditions of 60-70 DEG C, then at 80-100 DEG C, and 2- bromo caproic acid Arrcostab is added dropwise and is stirred to react
2h, layering obtain organic phase, steam solvent, obtain compound shown in formula 3；
B, compound shown in formula 3 that step A is obtained is dissolved in methanol, trimethyl orthoformate and p-methyl benzenesulfonic acid is then added,
It is stirred to react under the conditions of 20-30 DEG C 3 hours, adds sodium methoxide and be stirred to react 1h, steam solvent, obtain chemical combination shown in formula 4
Object；
C, compound shown in formula 4 that step B is obtained is dissolved in toluene, sodium hydroxide is added and is stirred under the conditions of 30-40 DEG C instead
It answers 4 hours, sodium chloride is then added, then salt acid for adjusting pH is added dropwise to 1-2, separate organic layer, obtain compound shown in formula 5；
D, compound shown in the formula 5 for obtaining step C is added in triethylamine, is warming up to 70-80 DEG C, paratoluensulfonyl chloride is added
Toluene solution 70-80 DEG C insulation reaction 2 hours, add sodium hydroxide, 70-75 DEG C keep the temperature 2 hours, stand, be layered, point
Organic phase out, dilute hydrochloric acid are washed to neutrality, steam solvent, intermediate 2- butyl benzofuran crude product shown in formula 2 are obtained, through subtracting
Pressure distillation obtains the fine work of 2- butyl benzofuran, structure as shown in Equation 2；
E, it under the conditions of -20 DEG C to -15 DEG C, into the mixture of anisoyl chloride, alchlor and halogenated hydrocarbons, is added dropwise
Enter intermediate 2- butyl benzofuran fine work shown in formula 2 obtained in step D, insulation reaction 1-8 hours, adds tri-chlorination
Aluminium is flowed back, is quenched, and 6 compound represented of formula is obtained；
F, 6 compound represented of formula obtained in step E is mixed with iodine, low-carbon alcohols, water and potassium carbonate, is reacted at 40-65 DEG C
8-10 hours, sodium sulfite quenching reaction is added, adjusts pH to 1-6, filters, obtains 7 compound represented of formula；
G, by 7 compound represented of formula obtained in step F and the chloro- N of 2-, N- diethylethanamine hydrochloride, potassium carbonate, Shui Hejia
Benzene is uniformly mixed, and is stirred to react 4h, is stood, and organic phase is washed in layering, and adjusting organic phase pH with hydrochloric acid is 1-2, steams solvent,
Obtain Amiodarone Hydrochloride crude product as shown in Equation 1；
H, it by Amiodarone Hydrochloride crude product obtained in step G, is dissolved in the mixed liquor of methylene chloride and methanol, crosses silicagel column, warp
Acetone reflux mashing purification, obtains Amiodarone Hydrochloride fine work.
2. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in step, the 2- hydroxyl
The molar ratio of benzaldehyde and the Anhydrous potassium carbonate is 1:(2.5-3.5)；The Benzaldehyde,2-hydroxy and 2- bromocaproic acid alkyl
The molar ratio of ester is 1:(1.05-1.5), the mass ratio of the Benzaldehyde,2-hydroxy, polar non-solute and toluene is 1:(1-
1.5): (2-5).
3. a kind of preparation method of Amiodarone Hydrochloride according to claim 2, which is characterized in that the polar non-solute
For the mixture of one or both of n,N-Dimethylformamide, Isosorbide-5-Nitrae-dioxane, the 2- bromo caproic acid Arrcostab is
2- bromo methyl caproate.
4. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in stepb, the formula 3
The molar ratio of shown compound and trimethyl orthoformate, p-methyl benzenesulfonic acid and sodium methoxide is 1:(1.1-2.0): (0.01-
0.05): (0.01-0.05).
5. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in step C, the formula 4
Compound represented and the molar ratio of sodium hydroxide are 1:(1.1-1.5)；The sodium chloride and 4 compound represented of formula
Mass ratio is (0.1-0.4): 1.
6. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in step D, the formula 5
The molar ratio of shown compound and triethylamine, paratoluensulfonyl chloride and sodium hydroxide is 1:(1-1.1): (1-1.1): (1-1.1).
7. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in step E, the 2- fourth
Base benzofuran and the molar ratio of anisoyl chloride, alchlor, the alchlor being added again are 1:(1-1.1):
(1-1.2): the mass ratio of (1-1.1), the halogenated hydrocarbons and 2- butyl benzofuran is (2-6): 1；In step F, the formula 6
Compound represented and the molar ratio of iodine, potassium carbonate and sodium sulfite are 1:(2-2.5): (1-1.3): (0.1-0.7)；It is described low
The mass ratio of carbon alcohol and water, 6 compound represented of formula is (1-5): (1-3): 1.
8. a kind of preparation method of Amiodarone Hydrochloride according to claim 7, which is characterized in that described halogenated in step E
Hydrocarbon is the mixture of one or both of 1,2- dichloroethanes, chlorobenzene, in step F, the low-carbon alcohols be methanol, ethyl alcohol,
The mixture of one or more of normal propyl alcohol, isopropanol.
9. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in step G, the formula 7
Compound represented and the chloro- N of 2-, N- diethylethanamine hydrochloride, potassium carbonate molar ratio be 1:(1.03-1.1): (2.5-
3.5), the mass ratio of 7 compound represented of formula and water, toluene is 1:(1.3-2): (3-4.5).
10. a kind of preparation method of Amiodarone Hydrochloride according to claim 1, which is characterized in that in steph, the salt
The mass ratio of sour amiodarone crude product and methylene chloride, methanol, silica gel, acetone is 1:(5-20): (0-5): (1-20): (10-15).
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| CN108440470A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2- butyl -3- (4- hydroxy benzoyls) benzofuran |
| CN108675972B (en) * | 2018-08-01 | 2020-09-11 | 北京嘉林药业股份有限公司 | Preparation method of amiodarone hydrochloride intermediate 2-butyl benzofuran |
| CN109053652A (en) * | 2018-09-04 | 2018-12-21 | 北京深蓝海生物医药科技有限公司 | A kind of preparation method of Amiodarone Hydrochloride intermediate |
| CN109988132B (en) * | 2019-04-18 | 2020-12-01 | 浙江恒康药业股份有限公司 | Preparation method of amiodarone hydrochloride |
| CN110261508B (en) * | 2019-07-05 | 2022-03-11 | 合肥拓锐生物科技有限公司 | Analysis method of related substances in amiodarone hydrochloride raw material medicine |
| CN110672734B (en) * | 2019-08-28 | 2022-03-11 | 合肥拓锐生物科技有限公司 | Analysis method of related substances in amiodarone hydrochloride injection |
| CN111747913A (en) * | 2020-07-15 | 2020-10-09 | 深圳大学 | Synthesis method of deuterated amiodarone hydrochloride |
| CN113527236B (en) * | 2021-08-20 | 2022-12-23 | 苏州弘森药业股份有限公司 | Method for preparing amiodarone hydrochloride |
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