CN112375014A

CN112375014A - Oppicapone process impurity, preparation method and application

Info

Publication number: CN112375014A
Application number: CN202011491592.3A
Authority: CN
Inventors: 代毅; 柳强; 邓祥林; 严紫薇; 雷海燕
Original assignee: Chongqing Liujiang Pharmatech Co ltd
Current assignee: Chongqing Liujiang Pharmatech Co ltd
Priority date: 2020-12-17
Filing date: 2020-12-17
Publication date: 2021-02-19

Abstract

The invention discloses an impurity (I) in an olpcapone process, a preparation method and application thereof (shown as the following formula). The preparation method disclosed by the invention is low in cost and simple and convenient to operate, can be synthesized in a large amount, and provides a reference substance for qualitative and quantitative analysis of the impurities of the ompicaapone, so that a foundation is tamped for quality research of the ulipidapone medicine and preparation.

（I）。

Description

Oppicapone process impurity, preparation method and application

Technical Field

The invention belongs to the technical field of drug synthesis, and relates to an olppecapone process impurity, and a preparation method and application thereof.

Background

Parkinson's Disease (PD) is a common nervous system degenerative disease, and is common in the elderly, with the average age of about 60 years, and the onset of juvenile Parkinson's disease below 40 years being rare. The prevalence rate of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. The most prominent pathological change of parkinson's disease is the degenerative death of mesocerebral Dopaminergic (DA) neurons, which causes a marked reduction in striatal DA content and causes disease. The exact etiology of this pathological change is still unclear, and genetic factors, environmental factors, aging, oxidative stress, etc. may all be involved in the degenerative death process of PD dopaminergic neurons.

Olcapone is a third-generation catechol O-methyltransferase inhibitor (COMT), an enzyme that degrades levodopa before it is converted to dopamine, and COMT inhibitors are a newer class of drugs that are advanced to clinical treatment of PD following levodopa and dopamine receptor agonists. The COMT inhibitor can prolong and increase the bioavailability of levodopa, provide a more stable dopaminergic stimulation, enhance the efficacy of levodopa, accelerate the onset of action and reduce the total amount of levodopa required. At present, the COMT inhibitor is used as an auxiliary drug of levodopa to treat severe patients with obvious fluctuation symptoms. It also has good therapeutic effect on early stage disease, and is approved by European Union in 6 months in 2016 for marketing.

The existence of certain impurities in the medicine can greatly influence the medication safety, so that the establishment of a corresponding analysis method by directionally preparing target impurities has important significance for effectively controlling the quality of the bulk drugs and related preparations.

Disclosure of Invention

The synthetic process of the ompapone comprises the following steps:

DCC is used as a condensing agent in the process to promote the reaction, correspondingly, impurities are also generated, and control needs to be carried out in an intermediate or a bulk drug to control the quality of the bulk drug.

The invention provides an impurity of an oppicapone process, which is shown as a formula (I):

。

in another aspect, the present invention provides a method for preparing the impurities of the olppecapone process, comprising the steps of:

1) dissolving 5-nitrovanillic acid in a polar solvent;

2) adding dicyclohexylcarbodiimide to step 1);

3) heating and stirring to react to obtain the impurities of the olppecapone process.

In the present invention, the structure of 5-nitrovanillic acid is:

。

in an embodiment of the present invention, the preparation method further comprises a step of column chromatography purification after the reaction is completed, so as to obtain the olppecapone process impurity. Optionally, the eluent for the column chromatography is dichloromethane and methanol, and dichloromethane: methanol =20:1 (volume ratio).

In the above preparation method of the present invention, the polar solvent in step 1) is one of tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide, and preferably, is tetrahydrofuran.

In the preparation method of the invention, the molar ratio of the 5-nitrovanillic acid to the dicyclohexylcarbodiimide in the step 2) is 1 (1-2), preferably 1: 1.5.

In the above preparation method of the present invention, the heating or reaction temperature in step 3) is 60 to 80 ℃, preferably 67 to 70 ℃.

The invention provides an application of an olcapone process impurity formula (I) as an olcapone raw material medicine and a reference substance for quality research of preparations of the olcapone raw material medicine.

The beneficial results of the invention are:

the invention provides a structure of an olcapone process impurity (I) and a preparation method thereof, and the method can be used for preparing the olcapone impurity (I) in a large quantity and can be used as a reference substance for quality research.

Drawings

FIG. 1 shows the mass spectrum of impurities (I) of the olpcapone process.

FIG. 2 shows the hydrogen spectrum of impurity (I) of the oppiocapone process.

Detailed Description

Example 1 Synthesis of impurities (I) of the oppicapone Process

Adding 10.00g of 5-nitrovanillic acid (59.4 mmol) and tetrahydrofuran (100 mL) into a reaction bottle at room temperature, stirring to dissolve the mixture, adding 1.5 equivalents of dicyclohexylcarbodiimide, heating to 60-66 ℃, reacting for 3 hours, evaporating the reaction solution under reduced pressure, purifying the obtained oily substance by a column, and finally obtaining 17.44g of a target product with the yield of 70.0%, wherein the eluent is dichloromethane: methanol =20:1 (volume ratio).

Example 2 Synthesis of the impurities (I) of OPIPICONE

Adding 100.00g of 5-nitrovanillic acid (594 mmol) and dimethyl sulfoxide (1L) into a reaction bottle at room temperature, stirring to dissolve the mixture, adding 2 equivalents of dicyclohexylcarbodiimide, heating to 77-80 ℃, reacting for 3 hours, adding dichloromethane and water into the reaction liquid, extracting and washing, purifying the obtained oily matter through a column, and finally obtaining 154.20g of a target product with the yield of 61.7%, wherein the eluent is dichloromethane: methanol =20:1 (volume ratio).

¹H NMR (600 MHz, MeOD): δ 7.800(s, 1H), 7.388 (s, 1H) , 3.953 (s, 3H), 1.952 (s, 1H), 1.880 (d, 2H), 1.299 (m, 12H), 1.218～1.238(m, 4H), 1.180 (d, 1H), 0.922 (m, 2H).

MS (ESI⁺) : 420.0 [M+H]⁺。

Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A technical impurity of OPIPACUPON has structure as formula (I)

（I）。

2. The method of preparing impurities of the olppecapone process of claim 1, comprising the steps of:

1) dissolving 5-nitrovanillic acid in a polar solvent;

2) adding dicyclohexylcarbodiimide to step 1);

3. The preparation method according to claim 2, further comprising a step of column chromatography purification after the reaction is finished; optionally, the eluent for the column chromatography is dichloromethane and methanol, and dichloromethane: methanol =20:1 (volume ratio).

4. The method according to claim 2 or 3, wherein the polar solvent in step 1) is one of tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide, preferably tetrahydrofuran.

5. The preparation method of claim 2 or 3, wherein the molar ratio of the 5-nitrovanillic acid to the dicyclohexylcarbodiimide in the step 2) is 1 (1-2), preferably 1: 1.5.

6. The production method according to claim 2 or 3, wherein the heating and reaction temperature in the step 3) is 60 to 80 ℃.

7. Use of the olpopone process impurity of claim 1 as a reference for olpopone bulk drug substance and its formulation quality studies.