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Terbutaline sulfate intermediate, preparation method thereof, and method for preparing terbutaline sulfate from terbutaline sulfate intermediate

A technology for terbutaline sulfate and intermediates, applied in the field of medicinal chemistry, can solve problems such as difficulty in extracting terbutaline free base, decline in product quality and yield, unstable free base quality, etc., to avoid product quality and yield reduction, short reaction time and high product yield

Active Publication Date: 2020-08-07
成都瑞特恩科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned synthesis method mainly has the following disadvantages: first, it needs to carry out high-pressure reaction in the reactor, which requires high safety; second, although the reduction of carbonyl with sodium borohydride can avoid the pressurized reaction, the reaction solution after reduction Difficult to handle; since the borate and terbutaline free base or the salt formed by the free base and acid are particularly water-soluble, it is difficult to separate it from the aqueous solution ; The 3rd, adopt the mode of " first reducing-becoming vitriol later ", reduction condition is harsher, and terbutaline free base extraction difficulty is big, and free base property is extremely unstable, causes product quality and yield to decline; The 4th , the reaction needs to use a class of organic solvents such as chloroform and benzene

Method used

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  • Terbutaline sulfate intermediate, preparation method thereof, and method for preparing terbutaline sulfate from terbutaline sulfate intermediate
  • Terbutaline sulfate intermediate, preparation method thereof, and method for preparing terbutaline sulfate from terbutaline sulfate intermediate
  • Terbutaline sulfate intermediate, preparation method thereof, and method for preparing terbutaline sulfate from terbutaline sulfate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: preparation compound 2 (R' is acetyl group)

[0084] Add 76mL of dichloromethane and 38g of 3,5-diacetoxyacetophenone into the reaction flask with tail gas absorption device, after stirring and dissolving completely, add dropwise a few drops of bromine-dichloromethane mixed solution (bromine element 27g dichloromethane 27ml), insulated and stirred until acid gas (checked with wet pH test paper) escaped and cooled to below 10°C, kept warm and continued to add bromine-dichloromethane solution dropwise, and the spots of the raw materials monitored by TLC basically disappeared ( TLC monitoring method: Silicone GF 254 , Developing agent: dichloromethane-ethyl acetate (10:1), ultraviolet lamp 254nm color), stop the reaction. The reaction solution was washed with water until the pH of the aqueous layer was 6-7, the dichloromethane layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the residue wa...

Embodiment 2

[0085] Embodiment 2: preparation compound 2 (R' is acetyl group)

[0086] Add 236g of 3,5-diacetoxyacetophenone and 500mL of dichloromethane into a reaction flask with a tail gas absorption device, stir and dissolve completely, then add a few drops of a solution of 160g of bromine and 160ml of dichloromethane at room temperature, Insulate and stir until hydrogen bromide gas (check with wet pH test paper) escapes, then cool down to below 10°C, continue to add bromine dichloromethane solution dropwise, and the spots of raw materials monitored by TLC basically disappear (thin-layer monitoring method: silica gel GF 254 , Developing agent: dichloromethane-ethyl acetate (10:1), UV lamp 254nm color development), washed with water to pH 6-7, dried the organic layer with anhydrous magnesium sulfate, filtered, removed the solvent under reduced pressure, and added the residue to Crystallization from absolute ethanol yielded compound 2 with a yield of 246 g and a yield of 78%.

Embodiment 3

[0087] Embodiment 3: preparation compound 2 (R' is acetyl group)

[0088] Add 236g of 3,5-diacetoxyacetophenone and 472mL of dichloromethane into the reaction flask with tail gas absorbing device. After stirring and dissolving completely, add a few drops of 176g of bromine and 176mL of dichloromethane solution under stirring at room temperature. After hydrogen bromide gas (check with wet pH test paper) escapes, lower the temperature to below 10°C, continue to add bromodichloromethane solution dropwise, and the spots of the raw material will basically disappear under TLC monitoring (thin-layer monitoring method: silica gel GF 254 , Developing agent: dichloromethane-ethyl acetate (10:1), ultraviolet lamp 254nm color development), nitrogen or air to remove hydrogen bromide, water washing to pH6~7, organic layer dried over anhydrous magnesium sulfate, filtered, The solvent was removed under reduced pressure, and the residue was crystallized by adding absolute ethanol to obtain com...

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Abstract

The invention discloses a terbutaline sulfate intermediate, a preparation method thereof, and a method for preparing terbutaline sulfate from the terbutaline sulfate intermediate, and belongs to the technical field of medical chemistry. The novel method for preparing terbutaline sulfate is mild in reaction condition, high in yield and environment-friendly, and comprises the following steps: firstly, providing the terbutaline sulfate intermediate represented by formula I; and then carrying out hydrogenation reduction by taking 10% Pd / C as a catalyst and an alcohol-water solution as a solvent toobtain the terbutaline sulfate represented by formula II. The free alkali hydrochloride or hydrobromide in a formula I is converted into the compound of the formula I before hydrogenation reduction,and the terbutaline sulfate is directly obtained after hydrogenation reduction, so extremely unstable terbutaline free alkali is prevented from appearing independently, and the method has the advantages of mild reaction conditions, high product yield, high purity, low production cost and the like, and is beneficial to industrial production of the terbutaline sulfate.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a terbutaline sulfate intermediate, a preparation method thereof, and a method for preparing terbutaline sulfate by using the intermediate. Background technique [0002] Terbutaline, whose chemical name is 1-(3,5-dihydroxyphenyl)-2-tert-butylaminoethanol, is an adrenergic β2 receptor (β2 receptor) agonist, and is currently one of the main drugs. The drug is highly selective for β2 receptors and has little cardiac side effects, and is suitable for asthmatic patients with cardiovascular diseases such as hypertension and coronary heart disease. It has the advantages of high curative effect, quick onset, long acting time and small side effects. Inhalation therapy is the first choice for the clinical application of β2 receptor agonists, which is quite effective for patients with mild and moderate asthma, with few side effects. [0003] According to domestic ...

Claims

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Application Information

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IPC IPC(8): C07C225/16C07C221/00C07C67/287C07C69/16C07C45/63C07C49/84C07C213/06C07C215/60
CPCC07C225/16C07C221/00C07C67/287C07C45/63C07C213/06C07C69/16C07C49/84C07C215/60Y02P20/55
Inventor 杨远云张弘郑阳杨柳
Owner 成都瑞特恩科技有限公司
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