CN100408549C - Synthesis method of levorotatory albuterol hydrochloride - Google Patents
Synthesis method of levorotatory albuterol hydrochloride Download PDFInfo
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- CN100408549C CN100408549C CNB2005100295244A CN200510029524A CN100408549C CN 100408549 C CN100408549 C CN 100408549C CN B2005100295244 A CNB2005100295244 A CN B2005100295244A CN 200510029524 A CN200510029524 A CN 200510029524A CN 100408549 C CN100408549 C CN 100408549C
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Abstract
The process of preparing levosalbutamol hydrochloride with racemoid salbutamol as material includes the following steps: dewatering racemoid salbutamol in acetone to obtain compound I, resolving compound I with optically pure organic acid A in solvent of water consolute fatty alcohol to obtain compound II, dissociating compound II under the action of alkali to obtain compound III, deprotecting compound III in HCl solution to form salt, and refining to obtain levosalbutamol hydrochloride. The process of the present invention has facile material, simple operation and short reaction period, and is simple and suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of Levalbuterol hydrochloride.
Background technology
Panting is one of common sympton of respiratory system disease, especially is more common in bronchial asthma and asthmatic bronchitis, be the secretory product that causes of bronchospasm and tunica mucosa bronchiorum inflammation increase and myxedema due to the result of SAO.Pathogenesis of asthma mechanism is how relevant with the I allergic reaction type.Beta receptor hypofunction during the asthma morbidity.
Levalbuterol hydrochloride, its chemical name is: (R)-α
1-[[(1, the 1-dimethyl ethyl) amino] methyl]-4-hydroxyl-1,3-xylyl alcohol hydrochloride.
Salbutamol is a kind of beta receptor of adrenin very effectively agonist, and it has very high selectivity to β-1 and β-2 acceptor, is widely used in treatment of asthma at present.This type of beta receptor agonist is than other the little characteristics of beta receptor agonist toxic side effect.Pharmacology studies show that, Levalbuterol exceeds 80 times of (Hartley and Middlemis than the drug effect of dextrorotation salbutamol, J.Med.Chem.14,895-896,1997), and Levalbuterol absorption in vivo rate also than dextrorotation salbutamol height (Wetterlin, J.Med.Chem.15,1182-1183,1972).
At present, the synthesis technique comparative maturity of racemic salbutamol.The optical purity salbutamol mainly is with chemical method for splitting preparation.A kind of is direct Split Method, and promptly direct resolving racemic salbutamol is a resolving agent with Naproxen Base or tartrate, as document (Sepc.Chem.15,249-253,1995, CN1107380) technology of report.Another is indirect Split Method, promptly split salbutamol precursor such as document and patent (J.Med.Chem.14,895-896,1971, US5545745, US5399765 and WO95/32178) technology that discloses, and then obtain final optical purity salbutamol by several steps reactions.The third is U.S. Pat 6365756 disclosed technology, will prepare salbutamol by splitting behind two hydroxyl protections of racemization salbutamol, and optical purity is lower.
The top required quantity of solvent of method is big, and process is loaded down with trivial details, extracts the salbutamol difficulty from water, is not easy suitability for industrialized production.
Summary of the invention
The technical issues that need to address of the present invention are the methods that disclose a kind of directly synthetic Levalbuterol hydrochloride, to overcome the above-mentioned shortcoming that prior art exists.
Method of the present invention comprises the steps:
(1) in the inert atmosphere,, adds the boron trifluoride diethyl etherate dehydration reaction, obtain compound (I) dissolving of racemization salbutamol and acetone;
Reaction times is 1～2 hour, and temperature of reaction is-10～10 ℃, and the mol ratio of racemization salbutamol and acetone is: the racemization salbutamol: acetone=1: 30～60; The mol ratio of racemization salbutamol and boron trifluoride diethyl etherate is: the racemization salbutamol: boron trifluoride diethyl etherate=1: 2.0～3.0;
Reaction expression is as follows:
(2) compound (I) splits with optically pure organic acid A reaction in solvent, obtain compound (II), reaction times is 2～3 hours, and temperature of reaction is 0～100 ℃, and compound (I) with the mol ratio of organic acid A is: compound (I): organic acid A=1: 0.5～0.7; Reaction expression is as follows:
Said solvent is the mixing solutions of the Fatty Alcohol(C12-C14 and C12-C18) of C1～C4 or itself and water, as methyl alcohol, ethanol, Virahol, and the mixture of isopropylcarbinol or itself and water;
The part by weight of the Fatty Alcohol(C12-C14 and C12-C18) of water and C1～C4 is:
The Fatty Alcohol(C12-C14 and C12-C18) of water: C1～C4=1: 0.3～4;
Said organic acid A is selected from optically pure tartrate, tartaric acid derivatives, D-(+)-dibenzoyl tartaric acid or D-(+)-4, a kind of in 4 '-dimethoxy dibenzoyl tartaric acid;
According to the present invention, the compound that obtains (II) is preferably in recrystallization in the Fatty Alcohol(C12-C14 and C12-C18) of C1～C4, preferentially selects methyl alcohol, ethanol, Virahol for use, and the mixture of isopropylcarbinol or itself and water obtains optically pure compound (II), is used for next step reaction then;
(3) add alkali in compound (II), hydrolysis obtains compound (III),
Reaction times is 1.0～2.0 hours, and temperature of reaction is 0～50 ℃, and compound (II) with the mol ratio of alkali is: compound (II): alkali=1: 2.5～3.5;
Said alkali is selected from yellow soda ash, sodium hydroxide, salt of wormwood, cesium carbonate, salt of wormwood, rubidium carbonate etc.; Reaction expression is as follows:
(4) HCl is added the mixture of compound (III) and solvent, deprotection salify, the refining then Levalbuterol hydrochloride that obtains;
Temperature of reaction is 0～60 ℃, and the reaction times is 6～10 hours, and the pH of reaction is 0.5～5;
Said solvent is a kind of or its mixture in alcohol, C2～C6 ester, C3～C6 ketone, C2～C6 ether or the hydrochloric ether etc. of C1～C6, as ethyl acetate, ethanol, methyl tertiary butyl ether; Reaction expression is as follows:
Method of the present invention, raw material is cheap and easy to get, and is simple to operate, and reaction time is short, does not need special equipment, and the three wastes are less, and finished product is stable, is fit to suitability for industrialized production.
Embodiment
Embodiment 1
The preparation of 2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol (I):
Racemization salbutamol (38g under the nitrogen protection; 0.16mol) adding acetone (400ml; 5.4mol) in; the cryosel cooling, and the dropping boron trifluoride diethyl etherate (43ml, 0.35mol); dropwise; it is that 0 ℃ 390g weight concentration is in 10% the sodium hydroxide solution, to stir that 0 ℃ of reaction 1h, reaction mixture are poured into temperature; excessive acetone evaporated under reduced pressure; ethyl acetate (150ml * 3) extraction merges organic phase, the saturated common salt water washing; anhydrous sodium sulfate drying; evaporated under reduced pressure obtains light yellow solid (I) 38g, yield: 85%, and need not purifying and be directly used in next step reaction.
Embodiment 2
The preparation of 2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol (I):
Racemization salbutamol (38g under the nitrogen protection; 0.16mol) adding acetone (800ml; 11mol); the cryosel cooling, and the dropping boron trifluoride diethyl etherate (59ml, 0.48mol); dropwise; it is that 0 ℃ 535g weight concentration is in 10% the sodium hydroxide solution, to stir that-10 ℃ of reaction 2h, reaction mixture are poured into temperature; excessive acetone evaporated under reduced pressure; ethyl acetate (150ml * 3) extraction merges organic phase, the saturated common salt water washing; anhydrous sodium sulfate drying; evaporated under reduced pressure obtains light yellow solid (I) 42g, yield: 94%, and need not purifying and be directly used in next step reaction.
Embodiment 3
(1), the preparation of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-dibenzoyl tartaric acid salt (II):
Methyl alcohol (135ml), join compound (I) (17g, 0.061mol) and D-(+)-dibenzoyl tartaric acid (11.8g, 0.033mol) mixture in, reflux 30min, cool to room temperature gradually in the 30min, stir 1h at 5 ℃, filter, solid is dried and is obtained white solid (II) 9.2g with ethyl acetate (20ml) washing, yield: 65% (to individual isomer), 88.8%ee
(2), the recrystallization of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-dibenzoyl tartaric acid salt (II)
With solid (the II) (9.2g that obtains among the embodiment 3.1,0.02mol) join methyl alcohol (135ml), reflux 2h, cool to room temperature gradually, 2 ℃ are stirred 1h, filter, solid is dried and is obtained white solid (II) with ethyl acetate (20ml) washing, repeats above operation and obtains white solid (II) 7.7g twice, yield: 54% (to individual isomer), 98.4%ee
Embodiment 4
With solid (the II) (9.2g that obtains among the embodiment 3.1,0.02mol) join in ethanol (100ml) water (50ml), reflux 2h, cool to room temperature gradually, 2 ℃ are stirred 1h, filter, solid is dried and is obtained white solid (II) with ethyl acetate (20ml) washing, obtains white solid (II) 6.7g, yield: 47% (to individual isomer), 99.1%ee
Embodiment 5
(1), the preparation of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-dibenzoyl tartaric acid salt (II):
Isopropylcarbinol (50ml), water (150ml) join compound (I) (17g, 0.061mol) and D-(+)-dibenzoyl tartaric acid (11.8g, 0.033mol) mixture in, reflux 30min, cool to room temperature gradually in the 30min, stir 1h at 10 ℃, filter, solid is dried and is obtained white solid (II) 8.2g with ethyl acetate (20ml) washing, yield: 58% (to individual isomer), 90%ee
(2), the recrystallization of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-dibenzoyl tartaric acid salt (II)
With solid (the II) (9.2g that obtains among the embodiment 5.1,0.02mol) join in isopropylcarbinol (50ml) water (150ml), reflux 2h, cool to room temperature gradually, 10 ℃ are stirred 1h, filter, solid washs with ethyl acetate (20ml), oven dry obtains white solid (II) 6.8g, yield: 48% (to individual isomer), 99.0%ee
Embodiment 6
(1), R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-4, the preparation of 4 '-dibenzoyl tartaric acid salt (II):
Virahol (60ml), water (120ml) join compound (I) (17g, 0.061mol) and D-(+)-4,4 '-dimethoxy dibenzoyl tartaric acid (16.8g, 0.040mol) mixture in, reflux 30min, cool to room temperature gradually in the 30min, stir 1h at 5 ℃, filter, solid is dried and is obtained white solid (II) 12.4g with ethyl acetate (20ml) washing, yield: 58% (to individual isomer), 90.5%ee
(2), R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol .D-(+)-4, the recrystallization of 4 '-dimethoxy dibenzoyl tartaric acid salt (II)
(9.2g 0.02mol) joins Virahol (60ml), in the water (120ml) with the solid (II) that obtains among the embodiment 6.1, reflux 2h, cool to room temperature gradually, 2 ℃ are stirred 1h, filter, solid washs with ethyl acetate (20ml), oven dry obtains white solid (II), repeats aforesaid operations twice, obtains white solid (II) 10.4g, yield: 47% (to individual isomer), 98.9%ee
Embodiment 7
The preparation of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol (III):
Compound (II) (210g, 0.46mol) join in water/ethyl acetate (1500ml/1500ml) mixing solutions, 25 ℃ add yellow soda ash (150g, 1.4mol), stir 1.5h, layering, water merges organic phase with ethyl acetate (1000ml * 2) extraction, with saturated salt solution washing, anhydrous sodium sulfate drying, evaporated under reduced pressure obtain white solid (III) 127g, yield: 99.2%
Embodiment 8
The preparation of R-2-(N-tertiary butyl amino)-1-(2,2-dimethyl-4H-benzo [1,3] dioxy-6-yl) ethanol (III):
Compound (II) (210g, 0.46mol) join in water/ethyl acetate (1500ml/1500ml) mixing solutions, 0 ℃ add sodium hydroxide (64.4g, 1.61mol), 30 ℃ are stirred 2h, layering, water merges organic phase with ethyl acetate (1000ml * 2) extraction, with saturated salt solution washing, anhydrous sodium sulfate drying, evaporated under reduced pressure obtain white solid (III) 125.5g, yield: 97%
Embodiment 9
The preparation of Levalbuterol hydrochloride:
Compound (III) (127g 0.455mol) is dissolved in the ethanol (500ml), 30 ℃ of temperature controls, and the adding weight concentration is 37% hydrochloric acid (39ml), the pH of reaction is 5; Reaction 8h adds ethyl acetate 1000ml, and be chilled to 10 ℃ and stir 1h down, suction filtration, the ethyl acetate washing obtains crude product 103g, yield: 82.4%.
Process for purification
Levalbuterol hydrochloride (100g) joins in the ethanol (950ml), and reflux adds ethyl acetate (540ml), backflow 30min to molten entirely, cooling gradually, solid is separated out, suction filtration, ethyl acetate washing, the decompression oven dry obtains highly finished product 74g, yield: 74%.mp＝185-187℃
Embodiment 10
The preparation of Levalbuterol hydrochloride
Compound (III) (127g 0.455mol) is dissolved in the ethanol (500ml), 30 ℃ of temperature controls, and the adding weight concentration is 37% hydrochloric acid (41ml), the pH of reaction is 0.5; Reaction 8h adds methyl tert-butyl ether 1000ml, and be chilled to 10 ℃ and stir 2h, suction filtration, the ethyl acetate washing obtains crude product 103g, yield: 82.4%.
Process for purification
Levalbuterol hydrochloride (10g) joins in the ethanol (100ml), and reflux adds methyl tert-butyl ether (50ml), backflow 30min to molten entirely, cooling gradually, solid is separated out, suction filtration, ethyl acetate washing, the decompression oven dry obtains highly finished product 7.7g, yield: 77%.mp＝185-187℃。
Claims (5)
1. the synthetic method of a Levalbuterol hydrochloride is characterized in that, comprises the steps:
(1) in the inert atmosphere,, adds the boron trifluoride diethyl etherate dehydration reaction, obtain compound (I) dissolving of racemization salbutamol and acetone;
Reaction times is 1～2 hour, and temperature of reaction is-10～10 ℃, and reaction expression is as follows:
(2) compound (I) splits with optically pure organic acid A reaction in solvent, obtains compound (II), and the reaction times is 2～3 hours, and temperature of reaction is 0～100 ℃, and reaction expression is as follows:
Said solvent is methyl alcohol, ethanol, Virahol, the mixture of isopropylcarbinol or itself and water;
(3) add alkali in compound (II), hydrolysis obtains compound (III),
Reaction times is 1.0～2.0 hours, and temperature of reaction is 0～50 ℃, and said alkali is selected from yellow soda ash, sodium hydroxide, salt of wormwood, cesium carbonate, rubidium carbonate etc.; Reaction expression is as follows:
(4) HCl is added the mixture of compound (III) and solvent, deprotection salify, the refining then Levalbuterol hydrochloride that obtains;
Temperature of reaction is 0～60 ℃, and the reaction times is 6～10 hours, and the pH of reaction is 0.5～5;
Reaction expression is as follows:
Salifiable solvent is a kind of or its mixture in alcohol, C2～C6 ester, C3～C6 ketone, C2～C6 ether or the hydrochloric ether of C1～C6.
2. method according to claim 1 is characterized in that, the mol ratio of racemization salbutamol and acetone is: the racemization salbutamol: acetone=1: 30～60; The mol ratio of racemization salbutamol and boron trifluoride diethyl etherate is: the racemization salbutamol: boron trifluoride diethyl etherate=1: 2.0～3.0.
3. method according to claim 1 is characterized in that, compound (I) with the mol ratio of organic acid A is: compound (I): organic acid A=1: 0.5～0.7; Said organic acid A is selected from optically pure tartrate, tartaric acid derivatives, D-(+)-dibenzoyl tartaric acid or D-(+)-4, a kind of in 4 '-dimethoxy dibenzoyl tartaric acid.
4. method according to claim 1 is characterized in that, compound (II) with the mol ratio of alkali is: compound (II): alkali=1: 2.5～3.5.
5. according to each described method of claim 1～4, it is characterized in that the compound that obtains (II) is recrystallization in the mixed solvent of the Fatty Alcohol(C12-C14 and C12-C18) of C1～C4 or itself and water, obtains optically pure compound (II), is used for next step reaction then.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018108089A1 (en) | 2016-12-14 | 2018-06-21 | 北京硕佰医药科技有限责任公司 | Class of bifunctional compounds with quaternary ammonium salt structure |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102260179A (en) * | 2010-05-24 | 2011-11-30 | 苏州睿克气雾医药有限公司 | Novel technology for resolving salbutamol sulfate |
| CN103896783A (en) * | 2012-12-27 | 2014-07-02 | 重庆华邦制药有限公司 | Recycling method of dextral impurities of levosalbutamol derivatives |
| CN104557572B (en) * | 2014-12-30 | 2017-02-22 | 上海默学医药科技有限公司 | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method |
| CN115109026A (en) * | 2022-06-28 | 2022-09-27 | 北京云鹏鹏程医药科技有限公司 | Preparation method of levalbuterol intermediate and hydrochloride with high ee value |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6365756B1 (en) * | 1998-02-20 | 2002-04-02 | Fine Chemical Corporation Limited | Process for the production of optically enriched (R)- or (S)-albuterol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6365756B1 (en) * | 1998-02-20 | 2002-04-02 | Fine Chemical Corporation Limited | Process for the production of optically enriched (R)- or (S)-albuterol |
Non-Patent Citations (2)
| Title |
|---|
| （R）沙丁胺醇的合成研究进展. 韩晓燕等.精细石油化工，第3期. 2002 |
| （R）沙丁胺醇的合成研究进展. 韩晓燕等.精细石油化工，第3期. 2002 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018108089A1 (en) | 2016-12-14 | 2018-06-21 | 北京硕佰医药科技有限责任公司 | Class of bifunctional compounds with quaternary ammonium salt structure |
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