CN114394962A - A kind of preparation method of N-desmethylzolmitriptan - Google Patents

Abstract

The invention discloses a preparation method of N-demethyl zolmitriptan, which is characterized in that the N-demethyl zolmitriptan is obtained by the reaction of zolmitriptan and demethylating reagent.

Description

A kind of preparation method of N-desmethylzolmitriptan

technical field

The invention belongs to the technical field of drug synthesis, and relates to a preparation method of N-desmethylzolmitriptan.

Background technique

Zolmitriptan, chemical name (S)-4-[3-[2-(dimethylamino)ethyl]-1H-indole-5-methyl]-2-oxazolidinone, is An anti-migraine drug developed by Glaxo-Wellcome in Germany, it is a highly selective serotonin (5-TH1B and 5-TH1D) receptor agonist, which stimulates intracranial blood vessels (including arteriovenous anastomosis) ) and 5-HTIB/ID receptors on the sympathetic nerves of the trigeminal nervous system, constrict blood vessels and inhibit the release of neuropeptides to relieve migraine attacks. At present, it has been listed in the United Kingdom, the United States and other countries, and the market prospect is good.

According to public information reports, zolmitriptan is mainly metabolized by the liver to indole acetic acid, N-oxide and N-desmethylzolmitriptan, of which indole acetic acid and N-oxide are inactive in the body, while The N-desmethyl metabolite is a serotonin 1D agonist with 2-6 times the activity of zolmitriptan. Therefore, in order to ensure the rational use of zolmitriptan and the safety of the ecological environment, it is of great significance to conduct in-depth research on N-desmethylzolmitriptan. The preparation method of N-desmethylzolmitriptan disclosed in the invention can provide important support for the research of zobiclone. The preparation method of N-desmethylzolmitriptan provided by the present invention has not yet been reported in the literature.

SUMMARY OF THE INVENTION

Object of the invention: In view of the above prior art, the present application provides a preparation method of N-desmethylzolmitriptan.

Technical scheme: in order to realize the above purpose, the present invention adopts the following scheme:

A preparation method of formula IIN-desmethylzolmitrip, the preparation method comprises reacting compound I with a demethylation reagent in an organic solvent to obtain compound II; the synthetic route thereof is as follows:

。

.

In an embodiment of the present invention, the present invention provides a method for preparing N-desmethylzolmitriptan, wherein the organic solvent is acetone or butanone.

In an embodiment of the present invention, in the preparation method of N-desmethylzolmitriptan provided by the present invention, the mass-volume ratio (g/ml) of the compound I to the organic solvent is 1:5-15.

In an embodiment of the present invention, in the preparation method of N-desmethylzolmitriptan provided by the present invention, the demethylation reagents are diethyl azodicarboxylate and diisopropyl azodicarboxylate Or di-tert-butyl azodicarboxylate.

In an embodiment of the present invention, the present invention provides a preparation method of N-desmethylzolmitriptan, wherein the reaction molar ratio of the compound I and the demethylation reagent is 1:1.5-5.

In an embodiment of the present invention, the present invention provides a method for preparing N-desmethylzolmitriptan, wherein the reaction temperature of the reaction is 0-50°C.

In an embodiment of the present invention, the present invention provides a preparation method of N-desmethylzolmitriptan, and the reaction time of the reaction is 6-24h.

The beneficial results of the present invention are:

The invention provides a preparation method of N-desmethylzolmitriptan represented by formula (II). The method can obtain the target product in one chemical reaction step, the separation steps are simple, the operation is convenient, and the N-desmethylzolmitriptan can be quickly prepared. Methylzolmitriptan can be used for studies on pharmacokinetics, raw material impurity identification, environmental control and protection. application value.

Detailed ways

Example 1

In a 500ml three-necked flask, add compound I (14.3g, 50mmol) and acetone (70ml), then nitrogen exchange three times, then slowly add diethyl azodicarboxylate (26.1g, 75mmol), react at room temperature for 12h, the reaction solution is concentrated, The residue was purified by column chromatography to obtain compound II.

Example 2

In a 500ml three-necked flask, add compound I (14.3g, 50mmol) and butanone (215ml), then nitrogen exchange three times, then slowly add di-tert-butyl azodicarboxylate (34.5g, 150mmol), react at 50°C for 6h, the reaction The liquid was concentrated, and the residue was purified by column chromatography to obtain compound II.

Example 3

In a 500ml three-necked flask, add compound I (14.3g, 50mmol) and acetone (180ml), then nitrogen exchange three times, then slowly add di-tert-methyl azodicarboxylate (36.5g, 250mmol), react at 0°C for 24h, the reaction solution After concentration, the residue was purified by column chromatography to obtain compound II.

¹ H NMR (400MHz, DMSO- d ₆ ) δ: 7.37 (s, 1H), 7.27 (d, 1H), 7.10 (s, 1H), 6.94 (d, 1H), 4.21-4.25 (m, 1H), 4.00-4.08 (m, 2H), 2.75-287 (m, 6H), 2.35 (s, 3H).

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.

Claims (7)

1. A preparation method of N-demethyl zolmitriptan is characterized in that the preparation method comprises the steps of reacting a compound I with a demethylation reagent in an organic solvent to obtain a compound II; the reaction route is as follows:

。

2. the method for preparing N-demethylzolmitriptan as claimed in claim 1, wherein the organic solvent is acetone or butanone.

3. The preparation method of N-demethylzolmitriptan as claimed in claim 1, wherein the mass-to-volume ratio (g/ml) of the compound I to the organic solvent is 1: 5-15.

4. The process of claim 1, wherein the demethylating agent is diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate.

5. The process for preparing N-demethylzolmitriptan as claimed in claim 1, wherein the molar ratio of compound i to demethylating agent is 1: 1.5-5.

6. The process for preparing N-demethylzolmitriptan as claimed in claim 1, wherein the reaction temperature is 0-50 ℃.

7. The method for preparing N-demethylzolmitriptan as claimed in claim 1, wherein the reaction time is 6-24 h.