CN102617404A - Preparation processes of bambuterol hydrochloride and intermediate thereof - Google Patents
Preparation processes of bambuterol hydrochloride and intermediate thereof Download PDFInfo
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Abstract
The invention relates to preparation processes of bambuterol hydrochloride and an intermediate thereof. The bambuterol hydrochloride is synthesized by taking 3,5-dihydroxyacetophenone as a starting raw material and undergoing esterifying, brominating, reducing, condensing and salting reactions. Compared with other processes, the process has the advantages that: the technical problems of industrial production are solved, each step of reaction is simple, and conditions are mild; and the process is a preparation process with the lowest cost at present, and is successfully applied to industrial production.
Description
Technical field
The invention belongs to organic chemistry filed, specifically is with 3, and the 5-resacetophenone is a starting raw material, through the preparation technology of esterification → bromo → reduction → condensation → 5 step of salify reaction synthesis of high purity KWD-2183 and midbody thereof.
Background technology
KWD-2183 is a kind of long-acting beta
2Receptor stimulant.The KWD-2183 formal name used at school be 1-[two-(3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl]-uncle's 2-N-fourth monoethanolamine hydrochloride, structural formula is:
This medicine is the bronchodilator of new generation that Switzerland Astra company developed in 1989, is used to treat bronchial asthma, is treatment one of asthma, pulmonary emphysema and bronchitic main medicine.Bambuterol is the double carbamate prodrug of terbutaline, and close ester property is strong, but after oral precedence partition in lung tissue; Reduce first-dose response, slowly hydrolysis produces terbutaline in lung tissue, thereby in blood, produces the terbutaline concentration that steadily continues; Effect can reach 24 hours; Obey once every night, easy to use, be present action time of the longest β
2Receptor stimulant.The untoward reaction of these article is lighter, and the degree of trembling and frequency all are lower than terbutaline, in outbreak of night or morning or the asthma patient that increases the weight of very big medical value is arranged to often being easy to.
Bambuterol is usually with the prepare and the sale of hydrochloride.The synthetic route of EP43807 report KWD-2183 is with 3, and the 5-resacetophenone is a starting raw material, through esterification, bromo; Again with the t-butyl benzylamine react 3,5-two (N, TMSDMA N dimethylamine methanoyl)-ω-N-benzyl-t-butyl aminoacetophenone; Again with the pd/c hydrogenolysis of pressurizeing, total recovery 20%, this preparation were established is loaded down with trivial details; The actually operating difficulty is big, and there are many problems in aftertreatment, therefore is difficult to obtain high-purity product.Domestic synthetic bibliographical information is more assorted, and quality product and yield are also unstable, and only are confined to laboratory scale, does not see the suitability for industrialized production report.
For this reason; The object of the invention is the preparation technology that KWD-2183 and midbody thereof are provided, and with 3, the 5-resacetophenone is a starting raw material; Through esterification → bromo → reduction → condensation → salify 5 step reaction synthetic hydrochloric acid bambuterol; Compare with other technology, the reaction of five steps all has innovation to improve, and five go on foot the level that the reaction theory yields have met or exceeded the domestic and foreign literature report.
Summary of the invention
The technical issues that need to address of the present invention are to overcome the technological difficulties that prior art can not be used for suitability for industrialized production, and the preparation technology of a kind of KWD-2183 and midbody thereof is provided, and this technology respectively goes on foot easy reaction; Mild condition; Solved the technological difficulties of suitability for industrialized production, KWD-2183 purity is high, and yield is high; With low cost, be successfully applied to suitability for industrialized production at present.
The present invention implements through following reaction.
It is starting raw material that the present invention adopts compound I, through esterification → bromo → reduction → condensation → synthetic object VI (KWD-2183) of salify 5 step reaction.
The present invention includes the following step:
One, esterification
1, N, N-dimethylaminoethyl chloride consumption is to the influence of reaction
Investigate N, N-dimethylaminoethyl chloride consumption is to the influence of reaction, and the result sees table one.
Table one: N, N-dimethylaminoethyl chloride consumption is to the influence of reaction
 | Chemical compounds I (g) | N, N-dimethylaminoethyl chloride (g) | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 30.4 | 56 | 57.5 | 80 | 97.8 |
| 2 | 30.4 | 70 | 58 | 94 | 98.6 |
| 3 | 30.4 | 84 | 60 | 96 | 102 |
[0010]Reaction conditions: chemical compounds I 0.2mol, Anhydrous potassium carbonate 0.4mol, ETHYLE ACETATE 220ml, 85 ℃ of temperature, 7 hours time.
Product content is earlier with N, and N-dimethylaminoethyl chloride consumption increases and very fast increasing, and when consumption restrained greater than 84, content was no longer obvious, in order to reduce production costs, confirms N, and N-dimethylaminoethyl chloride mol ratio consumption is 3.9.
, action solvent to the reaction influence
Investigate and use the influence of different action solvents to reaction, the result sees table two.
Table two: action solvent is to the influence of reaction
 | Chemical compounds I (g) | Action solvent | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 20 | Pyridine | 29 | 90 | 58 |
| 2 | 30.4 | ETHYLE ACETATE | 60 | 96 | 102 |
External synthetic bibliographical information uses pyridine to do action solvent, and theoretical yield is 61.4%; ETHYLE ACETATE is done action solvent, and the report theoretical yield can reach about 70%, through a series of tests relatively, confirms that ETHYLE ACETATE does action solvent.
, the Anhydrous potassium carbonate place of production to the reaction influence
Investigate the influence of the Anhydrous potassium carbonate place of production to reaction, the result sees table three.
Table three: the Anhydrous potassium carbonate place of production is to the influence of reaction
 | Chemical compounds I (g) | The Anhydrous potassium carbonate place of production | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 30.4 | Guangdong | 59.2 | 80 | 100 |
| 2 | 30.4 | Guangdong | 55.8 | 78 | 94.9 |
| 3 | 30.4 | Jiangsu | 60 | 96 | 102 |
| 4 | 30.4 | Jiangsu | 60 | 95.7 | 102 |
Through a series of tests, confirm that Jiangsu, the Anhydrous potassium carbonate place of production is superior to Guangdong, analyzing reason maybe be relevant with the Anhydrous potassium carbonate particle size.
, temperature of reaction to the reaction influence
Investigate the influence of temperature of reaction to reaction, the result sees table four.
Table four: temperature of reaction is to the influence of reaction
 | Chemical compounds I (g) | Temperature of reaction (℃) | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 37.6 | 50 | / | / | / |
| 2 | 37.6 | 85 | 59 | 90 | 81 |
The result of table four shows that temperature of reaction is obvious to the influence of reaction, and temperature is crossed low even can not get product, and temperature of reaction keeps back flow reaction for about 85 ℃, stable reaction, so temperature of reaction should be controlled at about 85 ℃.
, the reaction times to the reaction influence
Investigate the influence of reaction times to reaction, the result sees table five.
Table five: the reaction times is to the influence of reaction
Prolong the reaction times, can improve yield, but after arriving certain hour, it is stable that product content and yield keep, and explains that at this moment reaction reaches balance basically, the 8 hours proved response time of experiment can guarantee best product content and product yield.
, reaction theory yield and external synthetic document theoretical yield relatively
This reaction theory yield has reached 100%, and abroad the theoretical yield of synthetic bibliographical information is 61.4%.
Two, bromo-reaction
1, action solvent is to the influence of reaction
Investigate and use the influence of different action solvents to reaction, the result sees table six.
Table six: action solvent is to the influence of reaction
 | Compound ii (g) | Action solvent | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 30 | Dioxane | 34 | 92 | 93 |
| 2 | 30 | Methylene dichloride | 18.5 | 91 | 53 |
| 3 | 20 | Trichloromethane | 8 | 90 | 31.5 |
| 4 | 20 | Ethylene dichloride | 6 | 90 | 23.6 |
External synthetic bibliographical information uses dioxane to do action solvent, and theoretical yield is 76.2%, and trichloromethane is done action solvent, and the report theoretical yield can reach about 30%, through a series of tests relatively, confirms that dioxane does action solvent.
, bromizating agent to the reaction influence
Investigate and use the influence of different bromizating agents to reaction, experimental result is seen table seven.
Table seven: bromizating agent is to the influence of reaction
 | Compound ii (g) | Bromizating agent | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 30 | Bromine | 34 | 92 | 93 |
| 2 | 70 | The pyrrolidone bromine | 48.5 | 91 | 54.6 |
Test-results shows that the pyrrolidone bromizating agent is also more satisfactory to reaction, but does not have this production marketing on the market, and the self-control cost through overtesting relatively, confirms to use bromine than higher.The bromizating agent consumption is to the influence of content,
Reaction conditions: compound ii 0.1mol, dioxane 160ml, 40 ℃ of temperature, 3 hours time.Product content increases with the bromizating agent consumption earlier, and when consumption during greater than 5.1ml, product content begins decline, and by product increases, and therefore, confirms that the bromizating agent consumption is 5.1ml.
, temperature of reaction is to the influence of yield
Investigate the influence of temperature of reaction to yield,
Reaction conditions: compound ii 0.1mol, bromizating agent 5ml, dioxane 160ml, 3 hours time.Temperature of reaction is obvious to the influence of yield, and temperature is low excessively, and yield is not high, and temperature is too high, and by product increases, and yield descends, and confirms that therefore optimal reaction temperature is 40 ℃.
, the reaction times is to the influence of content
Investigate the influence of reaction times to content.
Reaction conditions: compound ii 0.1mol, bromizating agent 5ml, dioxane 160ml, 40 ℃ of temperature of reaction.
1 hour reaction times both can reach optimum reaction condition, and internal reaction was stable in 3 hours, reacted after 4 hours, and product content progressively descends, and by-products content increases.Therefore definite reaction times was advisable with 1 hour.
, post-treating method to the reaction influence
Investigate the influence of post-treating method to reaction, the result sees table eight.
Table eight: post-treating method is to the influence of reaction
 | Compound ii (g) | Post-treating method | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 30 | The hydrolysis crystallization | 37 | 91 | 97 |
| 2 | 30 | The distillation crystallization | 22.7 | 90 | 59.6 |
Can be known that by table eight the hydrolysis crystallization is simple, and is easy to operate, yield is high; And distillation crystallization trivial operations, loss is bigger, and yield is not high, therefore confirms to adopt the method for hydrolysis crystallization.
, reaction theory yield and external synthetic document theoretical yield relatively
This reaction theory yield can reach about 90%, and abroad the theoretical yield of synthetic bibliographical information is 76.2%.
Three, reduction reaction
1, catalyzer is to the influence of reaction
Investigate the influence of different catalysts to reaction, the result sees table nine.
Table nine: catalyzer is to the influence of reaction
 | Compound III (g) | Catalyzer | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 11.2 | Aluminum isopropylate | 3.2 | 53 | 28.4 |
| 2 | 11.2 | Peng Qinghuana | 12.5 | 86 | 111 |
| 3 | 11.2 | POTASSIUM BOROHYDRIDE 97MIN | 11.5 | 65 | 102 |
Visible from table nine, through a series of test contrasts, the sodium borohydride catalyzing best results, therefore definite Peng Qinghuana is done reducing catalyst.Catalyst levels is to the influence of content.
Reaction conditions: compound III 0.03mol, absolute ethyl alcohol 100ml, 60 ℃ of temperature, 3 hours time.
Product content increases with catalyst levels earlier, and as consumption＞0.9g, during consumption＜3g, product content is stable, and when consumption＞3g, product content begins to descend, and by product increases, and therefore definite catalyst levels is 0.96g.
, action solvent to the reaction influence
Investigate the influence to reaction of different sorts and proportioning action solvent, the result sees table ten.
Table ten: action solvent is to the influence of reaction
 | Compound III (g) | Action solvent | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 11.2 | DMF | 10 | 64 | 88 |
| 2 | 11.2 | The DMF+ Virahol | 8 | 66 | 71 |
| 3 | 11.2 | DMF+ Virahol+methylene dichloride | 11.5 | 60 | 102 |
| 4 | 11.2 | Virahol+methylene dichloride | 8.5 | 62 | 75 |
| 5 | 11.2 | Absolute ethyl alcohol+methylene dichloride | 9 | 72 | 79.9 |
| 6 | 11.2 | Virahol | 10.2 | 68 | 90.6 |
| 7 | 11.2 | Absolute ethyl alcohol | 10.5 | 90 | 93.0 |
Visible from table ten, investigate various action solvents and proportioning thereof and show that reaction is all had certain influence, but the more satisfactory still single solvent of effect, through a series of tests relatively, confirm that absolute ethyl alcohol does the optimum response solvent.
, temperature of reaction is to the influence of content
Investigate the influence of temperature of reaction to content,
Reaction conditions: compound III 0.03mol, Peng Qinghuana 1g, absolute ethyl alcohol 100ml, 3 hours time.
Temperature of reaction is obvious to the influence of content, and temperature is low excessively, and content is not high, and temperature is too high, and by product increases, and content descends, and confirms that therefore optimal reaction temperature is 40 ℃.
, the reaction times is to the influence of content
Investigate the influence of reaction times to content,
Reaction conditions: compound III 0.03mol, Peng Qinghuana 1g, absolute ethyl alcohol 100ml, 40 ℃ of temperature.
1 hour reaction times both can reach optimum reaction condition, and along with the prolongation in reaction times, product content progressively descends, and by-products content increases.Therefore definite reaction times was advisable with 1 hour.
, reaction theory yield and external synthetic document theoretical yield relatively
This reaction theory yield can reach about 90%, and external synthesis technique is to reduce after the first amination, therefore can't do similar reaction relatively.
Four, amination reaction
1, action solvent is to the influence of reaction
Investigate the influence of action solvent to reaction, the result sees table ten one.
Table ten one: action solvent is to the influence of reaction
| Compound IV (g) | Action solvent | Product must be measured (g) | Product content (%) | Product yield (%) | |
| 1 | 10.5 | Chloroform | 8.6 | 57 | 83.7 |
| 2 | 10.2 | Acetone | 7.5 | 53 | 75.1 |
| 3 | 10.5 | Virahol | 10 | 67 | 97.3 |
Through overtesting relatively, the differential responses solvent all has certain effect to reaction, and the definite Virahol of contrast is done action solvent.
, temperature of reaction is to the influence of yield
Investigate the influence of temperature of reaction to yield.
Reaction conditions: compound IV 0.028mol, TERTIARY BUTYL AMINE 7ml, Virahol 60ml, 18 hours time.
Elevated temperature, product yield increases, and confirms that therefore temperature of reaction is 85 ℃.
, the reaction times is to the influence of content
Investigate the influence of reaction times to content
[0052]Reaction conditions: compound IV 0.028mol, TERTIARY BUTYL AMINE 7ml, Virahol 60ml, 85 ℃ of temperature.
The reaction times prolongation is the balance ascendant trend to product content, and 16 hours reaction times reached optimum value, continues time expand, and product content is slow downtrending.Therefore definite reaction times was advisable with 16 hours.
, reaction theory yield and external synthetic document theoretical yield comparison
This reaction theory yield has reached 100%, and external synthesis technique is to reduce after the first amination, therefore can't do similar reaction relatively.
Five, salt-forming reaction
1, the hydrochloric acid classification is to the influence of reaction
Investigate the other influence to reaction of different salt acids, the result sees table ten two.
Table ten two: the hydrochloric acid classification is to the influence of reaction
| Compound V (g) | The hydrochloric acid classification | Product must be measured (g) | Product content (%) | Product yield (%) | |
| 1 | 276 | Hydrogen chloride gas | 203 | 91 | 66.98 |
| 2 | 170 | Aqueous hydrochloric acid | 102.2 | 98.9 | 54.7 |
Visible by table ten two, can adopt hydrogen chloride gas or aqueous hydrochloric acid salify all can with requiring according to the different production condition.
, action solvent to the reaction influence
Investigate the influence of action solvent to reaction, the result sees table ten three.
Table ten three: action solvent is to the influence of reaction
 | Compound V (g) | Action solvent | Product must be measured (g) | Product content (%) | Product yield (%) |
| 1 | 10.2 | Ether | 2.3 | 78 | 20.5 |
| 2 | 10.5 | Virahol+sherwood oil | 7 | 91 | 60.7 |
Through overtesting contrast, confirm that action solvent is advisable with Virahol and sherwood oil mixed solvent.
, reaction theory yield and external synthetic document theoretical yield comparison
KWD-2183 bullion theoretical yield can reach 50.2%, and the elaboration theoretical yield can reach 45%, and abroad the elaboration theoretical yield of synthetic bibliographical information is 21.2%.
Six, product analysis
The product that obtains by above-mentioned compound method is a white crystalline powder, conforms to the national new drug quality standard of KWD-2183 medicine.
The present invention has following advantage:
1. compound I (3, the 5-resacetophenone), existing market has raw material supply, and is cheap, do not need to prepare separately;
2. each step reaction is simple, and esterification and condensation reaction yield can reach 100%, and bromo-reaction and reduction reaction yield also can reach more than 90%, avoids the use of the tert-butyl amine and the pressure hydration reduction debenzylation of benzyl protection, has simplified experimental procedure and starting material;
3. operational condition is gentle, and HTHP has all been avoided in the reaction of five steps, has shortened the reaction times, has alleviated workman's operation easier;
4. product yield is high, five step reaction product bullion yield >=50.2%, and product elaboration yield >=45% improves more than 10 percentage points than external technology of synthesizing bibliographical information, has reduced production cost significantly;
5. gained KWD-2183 good product quality, product is a white crystalline powder, HPLC purity can reach>=and 99.5%, single foreign matter content≤0.1%.
Embodiment
Below each embodiment further specify the present invention, but do not do any restriction.
Embodiment 1: two-3,5-(N, N-formyl oxygen dimethylamino) methyl phenyl ketone (compound ii)
In the 2000ml reaction flask, add 152g (1mol) compound I, 376g (2mol) Anhydrous potassium carbonate, 900ml ETHYLE ACETATE stirs; Add 280gN, the N-dimethylaminoethyl chloride, 100ml ETHYLE ACETATE washing charging opening, 75～80 ℃ of control reaction temperature were reacted 8 hours; Reaction finishes, and adds sodium chloride aqueous solution, layering, and organic layer is used the water washing secondary; Anhydrous sodium sulfate drying, organic layer is evaporated to dried, and crystallization gets compound ii bullion 293.5g; Yield is 99.8%, and bullion is refining with Virahol and sherwood oil mixed solvent, gets compound ii elaboration 229g, and the elaboration yield is 77.9%.
Embodiment 2: two-3 ', 5 '-(N, N-formyl oxygen dimethylamino)-2-bromoacetophenone (compound III)
In the 2000ml reaction flask, add 229g compound ii elaboration, the 700ml dioxane stirs; Add the dioxane bromine solutions (250ml dioxane+45ml bromine) for preparing, 100ml dioxane washing charging opening, control reaction temperature was reacted 6 hours about 40 ℃; Reaction finishes, and in the reaction solution impouring 2000ml zero(ppm) water, separates out a large amount of white solids, filters; Drying gets compound III bullion 270g, and yield is 93%.Bullion is refining with Virahol, gets compound III elaboration 179g, and the elaboration yield is 62%.
Embodiment 3:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-ethylene bromohyrin (compound IV)
In the 2000ml reaction flask, add 179g compound III elaboration, the 1300ml absolute ethyl alcohol stirs; Add the 15.5g Peng Qinghuana, 100ml absolute ethanol washing charging opening, control reaction temperature was reacted 3 hours about 60 ℃; Reaction is finished, and adds aqueous ammonium chloride solution, uses the dichloromethane extraction secondary, merges organic layer; Anhydrous sodium sulfate drying, be evaporated to dried, compound IV 170g, yield is 94%.
Embodiment 4:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-uncle's 2-N-fourth monoethanolamine (compound V)
In the 2000ml reaction flask, add 170g compound IV, the 600ml Virahol stirs, and adds the 95ml TERTIARY BUTYL AMINE; 100ml washed with isopropyl alcohol charging opening, control reaction temperature reacted 18 hours at 80～85 ℃, and reaction is finished, and added 800ml zero(ppm) water; Use dichloromethane extraction, divide water-yielding stratum, organic layer use anhydrous sodium sulfate drying, be evaporated to dried, must compound V 183g; Yield is 110%, and content is 78%, and the real 142.74g that gets is real that yield is 85.8%.
Embodiment 5:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-uncle's 2-N-fourth monoethanolamine hydrochloride (compound VI, KWD-2183)
In the 2000ml reaction flask, add 183g compound V, 400ml Virahol, 300ml sherwood oil; Stir, feed the hydrogen chloride gas of prepared fresh, white crystalline solid occurs in the question response liquid; Stop to feed hydrogen chloride gas, reaction is finished, and filters; Drying gets 116g compound VI KWD-2183 white solid bullion, and yield is 74.2%.Bullion is refining with Virahol, gets 83.5g KWD-2183 (compound VI) elaboration, and content is 99.8%, and yield is 53.4%.
Embodiment 6: two-3,5-(N, N-formyl oxygen dimethylamino) methyl phenyl ketone (compound ii)
In 100 liter reaction kettles, add the 4kg compound I, the 7.26kg Anhydrous potassium carbonate, 28 liter ETHYLE ACETATE start and stir; Add 11kgN, the N-dimethylaminoethyl chloride, 5 liter ETHYLE ACETATE washing charging opening, control reaction temperature was reacted 8 hours at 75～80 ℃; Reaction finishes, and adds sodium chloride aqueous solution, layering, and organic layer is used water washing secondary, anhydrous sodium sulfate drying; Be evaporated to dried, crystallization, compound ii 8.28kg, yield is 107%.
Embodiment 7: two-3 ', 5 '-(N, N-formyl oxygen dimethylamino)-2-bromoacetophenone (compound III)
In 100 liter reaction kettles, add the 8.28kg compound ii, 35 liter dioxane stir; Add the dioxane bromine solutions (14 liters dioxane+4.27kg bromine) that configures, 5 liter dioxane washing charging opening, control reaction temperature was reacted 1 hour about 40 ℃; Reaction finishes, and the reaction solution impouring is equipped with in the reaction kettle of 90kg zero(ppm) water, separates out a large amount of white solids; Filtration, drying get compound III 8.72kg, and two step yields are 88.9%.
Embodiment 8:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-ethylene bromohyrin (compound IV)
In 200 liter reaction kettles, add 8.72kg compound III, 56 liter absolute ethyl alcohols stir; Add the 688g Peng Qinghuana, 5 liter absolute ethanol washing charging openings, control reaction temperature was reacted 1 hour about 40 ℃; Reaction finishes, and adds aqueous ammonium chloride solution, uses the dichloromethane extraction secondary, merges organic layer; Anhydrous sodium sulfate drying, be evaporated to dried, compound IV 7.24kg, three the step yields be 73.4%.
Embodiment 9:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-uncle's 2-N-fourth monoethanolamine (compound V)
In 100 liter reaction kettles, add 7.24kg compound IV, 26 liter Virahols stir; Add the 2.4kg TERTIARY BUTYL AMINE, 5 liter washed with isopropyl alcohol charging openings, control reaction temperature was reacted 16 hours at 80～85 ℃; Reaction finishes, and adds 35 liter zero(ppm) water, uses dichloromethane extraction, divides water-yielding stratum; Organic layer is used anhydrous sodium sulfate drying, be evaporated to dried, compound V 7.26kg, four the step yields be 75%.
Embodiment 10:1-(two-3 ', 5 '-N, the N-formyl oxygen dimethylamino) phenyl-uncle's 2-N-fourth monoethanolamine hydrochloride (compound VI, KWD-2183)
In 100 liter reaction kettles, add 7.26kg compound V, 12 liter 1mol/ liter aqueous hydrochloric acids stir; Normal-temperature reaction 2 hours, reaction finishes, and is evaporated to dried; Adding 60 liter Virahols, to add thermosol clear, and cooling crystallization filters, drying; Get 4.36kg KWD-2183 elaboration, content is that 99.6%, five step total recovery is 45%.
Claims (7)
1. the preparation technology of KWD-2183 and midbody thereof
Carry out as follows:
1) chemical compounds I is in the action solvent system, and Anhydrous potassium carbonate exists down, and control reaction temperature and reaction times, with N, the N-dimethylaminoethyl chloride carries out esterification, and reaction finishes, and through aftertreatment, gets compound ii;
2) compound ii is in the action solvent system, and bromizating agent exists down, control reaction temperature and reaction times, carry out bromo-reaction, and reaction finishes, and through aftertreatment, gets the compound III;
3) the compound III is in the action solvent system, and catalyzer exists down, control reaction temperature and reaction times, carry out reduction reaction, and reaction finishes, and through aftertreatment, gets the compound IV;
4) the compound IV is in the action solvent system, control reaction temperature and reaction times, carry out condensation reaction with TERTIARY BUTYL AMINE, reaction finishes, through aftertreatment, the compound V;
5) the compound V is carried out to reactant salt with hydrochloric acid soln (or hydrochloric acid gas) in the action solvent system, and reaction finishes, through aftertreatment and refinement treatment, and the dry compound VI elaboration-KWD-2183 that gets.
2. the preparation technology of KWD-2183 according to claim 1 and midbody thereof is characterized in that: in the described step 1), and compound I and N; The consumption of N-dimethylaminoethyl chloride is 1:1～5 in molar ratio, preferred 1:3～4, and action solvent is selected from pyridine, ETHYLE ACETATE; Ethyl acetate, the Anhydrous potassium carbonate place of production is selected from Guangdong, Jiangsu, preferred Jiangsu; Temperature of reaction is 50～85 ℃; Preferable reaction temperature is about 85 ℃, and the reaction times is 5～10 hours, 8 hours preferred reaction time.
3. the preparation technology of KWD-2183 according to claim 1 and midbody thereof is characterized in that: described step 2), action solvent is selected from dioxane, methylene dichloride, trichloromethane, ethylene dichloride; Preferred dioxane, bromizating agent is selected from bromine, pyrrolidone bromine, preferred bromine; The bromizating agent consumption is 0.1～0.3 of a compound ii quality, and is preferred 0.2, and temperature of reaction is 30～50 ℃; Preferable reaction temperature is about 40 ℃, and the reaction times is 1～6 hour, and the preferred reaction time is 1 hour; Post-treating method is selected from hydrolysis crystallization, distillation crystallization, selective hydrolysis crystallization.
4. the preparation technology of KWD-2183 according to claim 1 and midbody thereof; It is characterized in that: in the described step 3), action solvent is selected from N (DMF), N (DMF)+Virahol, N (DMF)+Virahol+methylene dichloride, Virahol+methylene dichloride, absolute ethyl alcohol+methylene dichloride, Virahol, absolute ethyl alcohol, preferred absolute ethyl alcohol; Catalyzer is selected from aluminum isopropylate, Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN; Preferred Peng Qinghuana, catalyst levels is 0.08～0.2 of a compound III quality, preferred about 0.1; Temperature of reaction is 30～50 ℃; About 40 ℃ of preferable reaction temperature, the reaction times is 1～3 hour, and the preferred reaction time is 1 hour.
5. the preparation technology of KWD-2183 according to claim 1 and midbody thereof; It is characterized in that: in the described step 4), action solvent is selected from trichloromethane, acetone, Virahol, preferred Virahol; Temperature of reaction is 30～85 ℃; Preferable reaction temperature is 85 ℃, and the reaction times is 8～20 hours, and the preferred reaction time is 16 hours.
6. the preparation technology of KWD-2183 according to claim 1 and midbody thereof; It is characterized in that: in the described step 5); Action solvent is selected from ether, Virahol+sherwood oil; Preferred Virahol and sherwood oil mixed solvent, the hydrochloric acid classification is selected from hydrogen chloride gas, aqueous hydrochloric acid, can adopt hydrogen chloride gas or aqueous hydrochloric acid salify all can with requiring according to the different production condition.
7. refining solvent is selected from Virahol.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288670A (en) * | 2013-05-16 | 2013-09-11 | 南京医科大学第一附属医院 | Polyhydroxy benzophenone derivative and application thereof |
| CN104262202A (en) * | 2014-09-12 | 2015-01-07 | 广东东阳光药业有限公司 | Preparation process of bambuterol intermediate |
| CN104557614A (en) * | 2014-12-15 | 2015-04-29 | 广东东阳光药业有限公司 | Reduction method of amine |
| CN105254512A (en) * | 2015-11-10 | 2016-01-20 | 山东达因海洋生物制药股份有限公司 | Preparation method of terbutaline sulphate |
| CN105859589A (en) * | 2016-04-05 | 2016-08-17 | 深圳市康立生生物科技有限公司 | Preparation method of bambuterol impurity C |
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| CN107445866A (en) * | 2017-07-13 | 2017-12-08 | 上海昕盛医药科技有限公司 | A kind of KWD-2183 impurity D synthetic method |
| CN110988241A (en) * | 2019-12-16 | 2020-04-10 | 湖南九典制药股份有限公司 | Method for detecting and separating related substances in bambuterol |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288670B (en) * | 2013-05-16 | 2014-11-05 | 南京医科大学第一附属医院 | Polyhydroxy benzophenone derivative and application thereof |
| CN103288670A (en) * | 2013-05-16 | 2013-09-11 | 南京医科大学第一附属医院 | Polyhydroxy benzophenone derivative and application thereof |
| CN104262202A (en) * | 2014-09-12 | 2015-01-07 | 广东东阳光药业有限公司 | Preparation process of bambuterol intermediate |
| CN104557614A (en) * | 2014-12-15 | 2015-04-29 | 广东东阳光药业有限公司 | Reduction method of amine |
| CN104557614B (en) * | 2014-12-15 | 2017-01-04 | 广东东阳光药业有限公司 | A kind of method of reducing of amine |
| CN105254512A (en) * | 2015-11-10 | 2016-01-20 | 山东达因海洋生物制药股份有限公司 | Preparation method of terbutaline sulphate |
| CN105859589B (en) * | 2016-04-05 | 2018-09-28 | 深圳市康立生生物科技有限公司 | A method of preparing bambuterol impurity C |
| CN105859589A (en) * | 2016-04-05 | 2016-08-17 | 深圳市康立生生物科技有限公司 | Preparation method of bambuterol impurity C |
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN106187820B (en) * | 2016-07-02 | 2017-09-19 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN107445866A (en) * | 2017-07-13 | 2017-12-08 | 上海昕盛医药科技有限公司 | A kind of KWD-2183 impurity D synthetic method |
| CN110988241A (en) * | 2019-12-16 | 2020-04-10 | 湖南九典制药股份有限公司 | Method for detecting and separating related substances in bambuterol |
| CN110988241B (en) * | 2019-12-16 | 2022-07-22 | 湖南九典制药股份有限公司 | Method for detecting and separating related substances in bambuterol |
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