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Synthesis method of levosalbutamol hydrochloride

A technology of levosalbutamol hydrochloride and its synthesis method, which is applied in the field of medicinal chemistry, can solve the problems of high reagent toxicity and high risk factor, and achieve the effect of economical raw materials and convenient process operation

Pending Publication Date: 2022-05-27
南京恒道医药科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above methods all have the disadvantages of high reagent toxicity and high risk factor.

Method used

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  • Synthesis method of levosalbutamol hydrochloride
  • Synthesis method of levosalbutamol hydrochloride
  • Synthesis method of levosalbutamol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of 2,2-dimethyl-6-vinyl-4H-benzo[d][1,3]dioxin

[0026] Take a 1000mL flask, add 208g (1.0mol) of accurately weighed 1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanol, and start stirring. . Then slowly add 16 g (0.2 mol) of titanium dioxide, install a water separator and a water flow pipe, turn on the heating, keep the internal temperature at 120-130 °C, and stir for 12 hours. After the reaction is completed, the temperature is lowered to below 50 °C, the water separator is removed, the vacuum distillation device is changed, and the 120 °C (less than 100Pa) fraction is collected to obtain 2,2-dimethyl-6-vinyl-4H-benzo[d ][1,3]dioxin 180.7g, the yield is 95%.

[0027] Mass spectrum: EI (m / z): 190; H NMR spectrum: 1 HNMR (400MHz, CDCl 3 ) δ7.55 (d, J =4Hz, 1H), 7.11(s, 1H), 6.87(d, J =4Hz, 1H), 6.65~6.60(m, 1H), 5.63~5.60(m, 1H), 5.19~5.5(m, 1H), 4.59(s, 2H), 1.49(s, 6H).

Embodiment 2

[0028] Example 2 Synthesis of (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxin

[0029] Take a clean 5000mL three-necked flask, add 180.5g (0.95mol) of the compound 2,2-dimethyl-6-vinyl-4H-benzo[d][1,3]dioxin obtained in Example 1, Add 2000mL of acetonitrile to dissolve, then add 1,2:4,5-di-O-isopropylidene-BETA-D-erythro-2,3-dione-2,6-pyranose 49.1g (0.19 mol), add 876 g (1.43 mol) of potassium monopersulfate (Oxone) under stirring, and add an appropriate amount of potassium hydroxide after the addition to keep the pH of the system between 10 and 11, and continue to stir the reaction at 25 °C for 8 to 12 h. . After the reaction was completed, slowly poured into 2000 ml of purified water prepared in advance, fully stirred for 30 min, statically separated into layers, and collected the organic layer. Add 2000 ml of dichloromethane for extraction, combine the organic layers, wash with saturated sodium chloride solution, dry the organic layer with anhydrous sodium sulfat...

Embodiment 3

[0031] Example 3 (R)-2-(tert-butylamine)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanol D-(+) - Preparation of malate

[0032] Take a clean 5000mL three-necked flask, add the compound (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1, 3] Dioxin Take 196g (0.95mol) of a clean 5000mL three-necked flask, add 1000ml of ethanol to dissolve, then add 80.4g (1.1mol) of tert-butylamine, turn on stirring, and heat to reflux, react for 3h, and check the progress of the reaction by TLC. After the reaction, 127 g (0.95 mol) of D-(+)-malic acid was added in batches, and the stirring was continued for 2 h after the addition. Then cooled to 5~15°C, a large amount of solid was precipitated, stirred for 3h, filtered, the filter cake was washed with ethanol, the filter cake was collected and dried to obtain (R)-2-(tert-butylamine)-1-(2,2-dimethyl-4H) -Benzo[d][1,3]dioxin-6-yl)ethanol D-(+)-malate 372g white solid, yield 94.7%.

[0033] Mass spectrum: ESI (m / z): 280.1; H NMR spectrum: 1 HN...

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Abstract

The invention discloses a method for synthesizing levosalbutamol hydrochloride, which comprises the following steps: by taking 1-(2, 2-dimethyl-4H-benzo [d] [1, 3] dioxin-6-yl) ethanol as an initial raw material, firstly synthesizing 2, 2-dimethyl-6-vinyl-4H-benzo [d] [1, 3] dioxin through dehydration; the preparation method comprises the following steps: firstly, preparing the (R)-2, 2-dimethyl-6-(oxirane-2-yl)-4H-benzo [d] [1, 3] dioxin from the (R)-2, 2-dimethyl-6-(oxirane-2-yl)-4H-benzo [d] [1, 3] dioxin through epoxidation under the combined action of 1, 2: 4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-diketone-2, 6-pyranose, potassium monopersulfate and potassium hydroxide. The preparation method comprises the following steps: firstly, carrying out reaction and condensation on (R)-2-(2, 2-dimethyl-4H-benzo [d] [1, 3] dioxin-6-yl) ethanol and tert-butylamine, and salifying a product and D-(+)-malic acid to obtain (R)-2-(tert-butylamine)-1-(2, 2-dimethyl-4H-benzo [d] [1, 3] dioxin-6-yl) ethanol D-(+)- And finally, dissociating with ammonia water, and reacting with hydrogen chloride ethanol to obtain the final product levosalbutamol hydrochloride. The method has the advantages of simple and novel route, convenient operation, total yield of 85-90%, and no isomer content detection, and is suitable for large-scale production.

Description

Technical field: [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing levosalbutamol hydrochloride. Background technique: [0002] Levosalbutamol is a β2-adrenergic receptor agonist that mainly activates β2-adrenergic receptors on airway smooth muscle, leading to activation of adenylate cyclase and an increase in intracellular 3',5'-cyclic adenosine monophosphate (cAMP) concentration, thereby relaxing airway smooth muscle. In vitro studies have shown that the affinity of salbutamol L-form with β receptors is 100 times stronger than that of D-form, and most of the physiological effects of racemate are provided by L-form. At the same time, it has also been proved that the relaxation effect of low-dose levsalbutamol is equivalent to that of the racemate. Compared with the racemate, levalbuterol has a faster action, higher curative effect and less side effects. Therefore, the application of single-enantiomer l...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C213/08C07C215/60C07D319/08C07D407/04C07C51/41C07C59/245G01N30/02
CPCC07C213/02C07C213/08C07D319/08C07D407/04C07C51/412G01N30/02C07B2200/07C07C215/60C07C59/245Y02P20/55
Inventor 陈端腾陶义华凌岫泉穆加兵黄迎春
Owner 南京恒道医药科技股份有限公司
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