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Process for preparing ethambutol and ethambutol hydrochloride

A technology for ethambutol and ethanol, which is applied in the field of preparing ethambutol and ethambutol hydrochloride, can solve the problems of limiting the production progress of rolling material feeding in large production, difficult to control the feeding amount, and occupying a long time for equipment, so as to improve the solvent Recovery rate, high practical value, and the effect of reducing corrosion to equipment

Active Publication Date: 2016-04-20
NEW FOUNDER HLDG DEV LLC +2
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0008] Taking 1,2-epoxy-3-butene as the starting material to react and prepare ethambutol has the following disadvantages: 1,2-epoxy-3-butene is a gas raw material, which requires high equipment and is not easy Control its feeding amount, many process steps
[0010] At present, the most practical method is to directly condense (S)-2-aminobutanol and 1,2-dichloroethane to prepare ethambutol, but in the existing method, it is necessary to The temperature is raised to 130°C for condensation reaction, the amount of (S)-2-aminobutanol is high (the ratio of (S)-2-aminobutanol to 1,2-dichloroethane is as high as 16:1), and NaOH is used to The HCl produced by the neutralization reaction has a low yield, and NaOH is more corrosive to equipment (see (for example) the method described in US Patent Document US3769347)
[0011] Others, such as protecting the amino group first and then condensing, or generating The method of oxazolidine recondensation all has following deficiencies: increase raw material variety, increase operation, increase equipment, impurity is many, is difficult to apply in production
Therefore, this method takes a long time for the equipment and consumes a lot of energy, which limits the production progress of large-scale production rolling feeding

Method used

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  • Process for preparing ethambutol and ethambutol hydrochloride
  • Process for preparing ethambutol and ethambutol hydrochloride
  • Process for preparing ethambutol and ethambutol hydrochloride

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preparation example Construction

[0051] The method for preparing ethambutol hydrochloride of the present invention comprises utilizing (S)-2-aminobutanol and 1,2-dichloroethane to carry out condensation reaction to prepare ethambutol, wherein said condensation reaction is in a low-boiling point organic solvent carried out, and the HCl generated during the reaction was neutralized with ammonia gas.

[0052] The method may further include:

[0053] 1) Make excess (S)-2-aminobutanol and 1,2-dichloroethane undergo condensation reaction as shown in chemical reaction formula I to generate ethambutol and HCl:

[0054]

[0055] Wherein, the condensation reaction is carried out in a low-boiling point organic solvent, and the reaction temperature is 70-80°C;

[0056] 2) Neutralize the generated HCl with ammonia gas, and make the pH of the resulting reaction system 9-10;

[0057] 3) Separating the reaction system obtained in step 2) to obtain ethambutol.

[0058] (S)-2-aminobutanol and 1,2-dichloroethane are known...

Embodiment 1

[0101] Put 735.3ml (765g, 8.58mol) of (S)-2-aminobutanol and 114ml (90g) of absolute ethanol into a 1.5L reaction tank, stir to raise the temperature, control the temperature to 78°C, and slowly add 71.4 Add ml (90g, 1mol) of 1,2-dichloroethane within 2.5 hours, control the temperature at 80°C, and keep it warm for another 7 hours. The temperature was lowered to 58°C, and 42.6 g (2.5 mol) of ammonia gas was introduced slowly, and the addition was completed within 2.5 hours. Control the pH of the reaction solution to 9.7. The temperature was raised to 95°C to distill and recover 107ml (84.5g) of ethanol. Use vacuum distillation to recover 586.7ml (563.3g, 6.32mol) of (S)-2-aminobutanol at 153°C, and control the vacuum pressure to -0.09MPa, leaving 274g of the product in the tank. Cool down to 70°C, add 300ml (237g) of absolute ethanol, stir for 0.5 hours, filter with suction, filter off ammonium chloride (84.9g, 1.6mol), and obtain 425g (319ml) of ethambutol alcohol solution,...

Embodiment 2

[0103] Put 735.3ml (765g, 8.58mol) of (S)-2-aminobutanol and 114ml (90g) of anhydrous methanol into a 1L reaction tank, stir to raise the temperature, control the temperature to 78°C, and slowly add 90g ( 1mol) of 1,2-dichloroethane was added within 2.5 hours, and then kept for 7 hours. The temperature was lowered to 55°C, and 42.6g (2.5mol) of ammonia gas was introduced slowly, and the addition was completed dropwise within 2.5 hours, and the pH of the reaction solution was controlled to be 9.5. The temperature was raised to 95°C to recover 107.5ml (85g) of anhydrous methanol. 578.4ml (555.3g, 6.23mol) of (S)-2-aminobutanol was recovered by vacuum distillation at 154°C, the vacuum pressure was controlled at -0.09MPa, and 262g of the product remained in the tank. Cool down to 70°C, add 300ml (237g) of absolute ethanol, stir for 0.5 hours, filter with suction, filter off 83g (1.55mol) of ammonium chloride, obtain 416g (318ml) of ethambutol alcohol solution, and recover ethanol...

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Abstract

The invention provides methods for preparing ethambutol and ethambutol hydrochloride. The method for preparing the ethambutol comprises the step of utilizing (S)-2-aminobutanol and 1,2-dichloroethane to perform condensation reaction to prepare the ethambutol, wherein the condensation reaction is carried out in a low-boiling organic solvent, and HCl produced in the ammonia gas neutralization reaction process is utilized. Through the utilization of the method, the ethambutol of which the yield coefficient is improved can be obtained, so that the ethambutol hydrochloride of which the yield coefficient is improved can be obtained. Besides, the methods are simple in technology, safe, stable, low in cost and super-high in practical value in the industry.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing ethambutol and ethambutol hydrochloride. Background technique [0002] Ethambutol is the key intermediate of the chiral anti-tuberculosis drug ethambutol hydrochloride, which is widely used in combination with other anti-tuberculosis drugs to treat tuberculosis caused by Mycobacterium tuberculosis, and can also be used for tuberculous meningitis and atypical Treatment of mycobacterial infections. The drug accounts for more than 13% of the anti-TB drug market share. [0003] The chemical name of ethambutol (English name: Ethambutol) is [2R,2[S-(R * , R * )]-R](+)-2,2'-(1,2-Ethylenediimino)-bis-1-butanol, the molecular formula is: C 10 h 24 N 2 o 2 , the molecular weight is 204.31, the CAS number is 74-55-5, and its structural formula is: [0004] [0005] The hydrochloride form of ethambutol is ethambutol hydrochloride (English name:...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/14C07C213/08
Inventor 杨通明赵德李明川胡晓
Owner NEW FOUNDER HLDG DEV LLC
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