The preparation method of nevirapine

A technology of nevirapine and crude product, applied in the field of preparation of nevirapine, can solve the problems of large amount of diethylene glycol dimethyl ether, complicated operation and high boiling point of diethylene glycol dimethyl ether

Active Publication Date: 2016-07-20
SHANGHAI DESANO CHEM PHARMA +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] But this technique still has many disadvantages, for example, (1) after the compound shown in formula (III) reacts with cyclopropylamine, the reaction solution needs to be filtered and concentrated, and the operation is complicated; (2) the last two-step reaction of the above-mentioned technique uses diethylene glycol Alcohol dimethyl ether is used as a solvent, and the consumption of diethylene glycol dimethyl ether is large, and the boiling point of diethylene glycol dimethyl ether is high, and recovery is difficult, and the price is more expensive, and the production cost is high; (3) the last step reaction of the above-mentioned technique ( Ring closure reaction) uses sodium hydride as the base. As we all know, sodium hydride can spontaneously ignite in humid air, and when heated or in contact with moisture and acids, it will release heat and hydrogen to cause combustion and explosion

Method used

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  • The preparation method of nevirapine
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  • The preparation method of nevirapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Add toluene 200ml, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide (100.0g, 0.35mol), triethylamine (100ml, 0.72 mol), cyclopropylamine (51.0ml, 0.74mol), start stirring. Slowly raise the temperature to 130°C, and keep the reaction for 10 hours. After taking a sample to detect the remaining raw materials <2%, turn off the stirring, pass condensed water into the kettle to lower the temperature to room temperature, and obtain 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)- 3-Pyridinecarboxamide reaction mixture.

[0091] Open the autoclave, pour the above mixture into a reaction flask, add 100ml of diethylene glycol dimethyl ether, stir, cool down to 15°C, add sodium amide (44.0g, 1.13mol), and keep stirring for 10 minutes. Heat slowly to 110° C., and keep the reaction for 2 hours. After the raw materials were detected by TLC, the toluene was distilled off under reduced pressure. The residue was cooled to 20°C, 500ml of water was added dropwise, and...

Embodiment 2

[0094] Add 50ml of toluene, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide (10.0g, 0.035mol), triethylamine (12.0ml, 0.086mol), cyclopropylamine (5.0ml, 0.072mol), start stirring. Slowly raise the temperature to 135°C, and keep the reaction for 13 hours. After taking a sample to detect the remaining raw materials <2%, turn off the stirring, pass condensed water into the kettle to lower the temperature to room temperature, and obtain 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)- 3-Pyridinecarboxamide reaction mixture.

[0095] Open the autoclave, pour the above mixture into a reaction flask, add 15ml of diethylene glycol dimethyl ether, stir, cool down to 5°C, add potassium tert-butoxide (10.0g, 0.089mol), and keep stirring for 15 minutes. Heating is slowly raised to 100° C., and the reaction is kept for 3 hours. After the raw materials were detected by TLC, the toluene was distilled off under reduced pressure. The residue was cooled to 20°C, 60ml of w...

Embodiment 3

[0098] In the autoclave, add xylene 40ml, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide (10.0g, 0.035mol), diisopropylethylamine (12.5ml, 0.072mol), cyclopropylamine (6.0ml, 0.087mol), and start stirring. Slowly raise the temperature to 125°C, and keep it warm for 8 hours. After taking a sample to detect the remaining raw materials <2%, turn off the stirring, pass condensed water into the kettle to lower the temperature to room temperature, and obtain 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)- 3-Pyridinecarboxamide reaction mixture.

[0099]Open the autoclave, pour the above mixture into a reaction flask, add 20ml of diethylene glycol dimethyl ether, stir, cool down to 10°C, add sodium methoxide (7.5g, 0.14mol), and keep stirring for 15 minutes. Heat slowly to 115° C., and keep the reaction for 5 hours. After the reaction of raw materials was detected by TLC, xylene was distilled off under reduced pressure. The residue was cooled to 20°C, 60ml of ...

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Abstract

The invention discloses a preparation method for nevirapine. The method comprises the following steps: 1) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide with cyclopropylamine in an organic solvent in the presence of alkylamine so as to obtain a reaction mixture containing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide; and 2) mixing the reaction mixture obtained in the step (1) with an ether solvent or with a mixed solvent of the ether solvent and an aromatic hydrocarbon solvent in the presence of a base and allowing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide to undergo a cyclization reaction so as to obtain a reaction mixture containing nevirapine. The method may further comprise a step of nevirapine purification. The method provided by the invention has mild reaction conditions and is easy to control; process operation of the method is simple and safe; and the product nevirapine has good yield and high purity.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of nevirapine. Background technique [0002] Nevirapine is a non-nucleoside reverse transcriptase inhibitor (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI) of HIV-1, the chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridine And[3,2-b:2',3'-e][1,4]diazepine-6-one, its structural formula is shown in formula (I). [0003] [0004] The preparation method of nevirapine has been disclosed in the patent US5,366,972 earlier, as shown in Scheme 1. [0005] [0006] Process 1 [0007] The biggest shortcoming of this technique is that in the substitution reaction of compound (2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide) and cyclopropylamine shown in formula (III), cyclopropylamine The amount of used is too large (nearly 4 times the molar weight), it is easy to produce the by-product shown in the c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14
Inventor 李金亮赵楠吴俊
Owner SHANGHAI DESANO CHEM PHARMA
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