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Method for preparing dipivefrine

A technology of dipifolin and chloroacetyl catechol is applied in the preparation of organic compounds, chemical instruments and methods, preparation of aminohydroxy compounds, etc., and can solve the difficulty of post-processing, many side reactions, and large consumption of pivaloyl chloride and other problems, to achieve the effects of simple operation and post-treatment, mild reaction conditions and high reaction yield

Active Publication Date: 2013-06-19
TIANJIN KELUO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantages of this method are: many side reactions, long reaction time, large consumption of pivaloyl chloride and PtO 2 more expensive, high cost
The disadvantages of this method are: the cost of raw material adrenaline is high, the yield of intermediates is low, and post-processing is difficult

Method used

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  • Method for preparing dipivefrine

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Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1: the preparation of dipephrine

[0024] Add 600g (3.21mol) of 4-chloroacetylcatechol and 6L of dichloromethane into a 10L four-neck flask, cool the system down to 5°C, add 666g (6.58mol) of triethylamine, and then dropwise add 784g (6.5mol) ) pivaloyl chloride, continue to stir for 3h after the dropwise addition. Suction filtration and rotary evaporation of the filtrate; 990 g of a yellow-brown solid, namely phenyl 4-(2-chloroacetyl)-1,2-dipivalate, with a content of 96.2% was obtained.

[0025] Add 526g (4.35mol) of N-methylbenzylamine, 370g (3.66mol) of triethylamine, 25g (0.15mol) of KI, and 3L of DMF into a 10L four-necked flask. The temperature was lowered to 0°C, and a DMF solution of 990 g (2.8 mol) of 4-(2-chloroacetyl)-1,2-dipivaloic acid phenyl ester was added dropwise for 2 h. Stir at room temperature for 4h.

[0026] Suction filtration, add 10L water to the filtrate to wash 3 times, separate the organic phase, and rotary evaporate the organic...

Embodiment 2

[0034] Embodiment 2: the preparation of dipephrine

[0035] Add 600g (3.21mol) of 4-chloroacetylcatechol and 6L of dichloromethane into a 10L four-neck flask, cool the system down to 10°C, add 666g (6.58mol) of triethylamine, and then dropwise add 784g (6.5mol) ) pivaloyl chloride, continue to stir for 3h after the dropwise addition. Suction filtration, rotary distillation of the filtrate; 978.2 g of a yellow-brown solid, namely phenyl 4-(2-chloroacetyl)-1,2-dipivalate, with a content of 96.2% was obtained.

[0036] Add 526g (4.35mol) of N-methylbenzylamine, 370g (3.66mol) of triethylamine, 25g (0.15mol) of KI, and 3L of DMF into a 10L four-necked flask. The temperature was lowered to 0° C., and a DMF solution of 978.2 g (2.77 mol) of 4-(2-chloroacetyl)-1,2-dipivaloic acid phenyl ester was added dropwise for 2 h. Stir at room temperature for 4h.

[0037] Suction filtration, add 10L water to the filtrate and wash 3 times, separate the organic phase, and rotary evaporate the ...

Embodiment 3

[0042] Embodiment 3: the preparation of dipephrine

[0043] Add 600g (3.21mol) of 4-chloroacetylcatechol and 6L of dichloromethane into a 10L four-necked flask, cool the system down to 5°C, add 897g (6.5mol) of potassium carbonate, and then dropwise add 784g (6.5mol) Pivaloyl chloride, continue to stir for 5h after the dropwise addition. Suction filtration and rotary evaporation of the filtrate; 900 g of a yellow-brown solid, namely phenyl 4-(2-chloroacetyl)-1,2-dipivalate, with a content of 95.6% was obtained.

[0044] Add 526g (4.35mol) of N-methylbenzylamine, 414g (3.0mol) of potassium carbonate, 25g (0.15mol) of KI, and 3L of DMF into a 10L four-necked flask. The temperature was lowered to 0° C., and a DMF solution of 900 g (2.55 mol) 4-(2-chloroacetyl)-1,2-dipivalic acid phenyl ester was added dropwise for 3 h. Stir at room temperature for 6h.

[0045] Suction filtration, add 10L water to the filtrate and wash 3 times, separate the organic phase, and rotary evaporate t...

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Abstract

The invention relates to a method for preparing dipivefrine. The method comprises the following steps of: performing an esterification reaction of 4-chloroacetyl catechol serving as a raw material and pivaloyl chloride, and after performing a substitution reaction of the obtained product and N-methylbenzylamine, reducing by a reducing agent and performing catalytic hydrogenation to obtain the dipivefrine. The dipivefrine prepared by the method is an anti-glaucoma medicament, is mainly used for treating open-angle glaucoma and high intraocular pressure diseases, and has the effect on remainingglaucoma formed after the iridectomy of angle-closure glaucoma is performed and other types of secondary open-angle glaucoma and glaucomatocyclitic crisis. In the method, the 4-chloroacetyl catechol serving as the raw material has low cost, high reaction yield and high purity of over 98 percent, and the reaction condition is mild and operation and aftertreatment are simple, so the dipivefrine canbe prepared and produced commercially on a large scale to meet current constantly-increased market demands.

Description

technical field [0001] The invention relates to a preparation method of dipephrine. Background technique [0002] As an anti-glaucoma drug, dipifolin is mainly used for the treatment of open-angle glaucoma and ocular hypertension, residual glaucoma after iridectomy for angle-closure glaucoma and other types of secondary open-angle glaucoma and glaucoma Cyclitis syndrome is effective. US 3809714 has reported the preparation method of dipephrine, it is to use 4-chloroacetyl catechol as raw material and methylamine condensation, obtain epinephrine, then with pivaloyl chloride generation esterification reaction, obtain epinephrine dipipaphthyl ester, and then H 2 / PtO 2 restored. The disadvantages of this method are: many side reactions, long reaction time, large consumption of pivaloyl chloride and PtO 2 Relatively expensive, high cost. US 4,085,270 also only reported the step of palladium carbon catalytic hydrogenation to reduce 1-(3,4-dipivaloyloxyphenyl)-2-(N-benzylmet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C219/30C07C213/02
Inventor 陈波张术兵王文龙梅淑贞刘琪靳敏
Owner TIANJIN KELUO PHARMA
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