CN112279850B

CN112279850B - Preparation method of olapari impurity

Info

Publication number: CN112279850B
Application number: CN202011472892.7A
Authority: CN
Inventors: 周步高; 张明雨; 惠舰; 宁武松; 徐光辉
Original assignee: Nanjing F&s Pharmatech Co ltd
Current assignee: Nanjing Hengyang Pharmaceutical Co.,Ltd.
Priority date: 2020-12-15
Filing date: 2020-12-15
Publication date: 2021-04-02
Anticipated expiration: 2040-12-15
Also published as: CN112279850A

Abstract

The invention discloses a preparation method of an olapari impurity V. The compound V provided by the invention can be used as a reference substance for detecting related substances of the olaparide, and is used for controlling the purity of the crude drug of the olaparide and the preparation. The preparation method comprises the steps ofFormyl benzoic acid is used as an initial raw material, and the compound V is obtained through operations of condensation, substitution, dehydration and the like.

Description

Preparation method of olapari impurity

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of an olapari impurity.

Background

Olaparide is an inhibitor of poly (adenosine diphosphate ribose) polymerase (PARP), a DNA repair enzyme that plays a key role in the DNA repair pathway, and PARPi can produce anti-tumor activity through synthetic lethal effects.

Olaparide is approved for marketing in europe and the united states at 16 days 12/2014 and 19 days 12/2014, respectively, is the first worldwide marketed PARPi, and approved indications are recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer that is fully or partially responsive to platinum-based chemotherapy; advanced ovarian cancer associated with mutations in BRCA (gBRCAm) that are harmful or suspected to be harmful that have been treated with three or more chemotherapeutics; treating metastatic breast cancer patients who have been treated with harmful or suspected harmful mutations in BRCA (gBRCAm), HER 2-negative chemotherapy.

Currently, the general synthetic route for olapari is as follows:

in exploring the process conditions of the above synthetic route, the researchers found that the process may contain impurities of compound V, which may affect the purity of the olaparide bulk drug and need to be controlled during the synthesis of olaparide, thereby ensuring the quality of the olaparide bulk drug. Through the research on the impurity V, important reference can be provided for the quality of the intermediate in each step of the Olapari process. The impurity V, which is one of impurities in the synthesis process of olaparide, is low in content in the synthesis of olaparide, is difficult to separate, and is not favorable for obtaining a large amount of high-purity impurity reference substances.

Through literature research, we found that only one literature reports the synthesis method of compound V (arch. pharm., 1982, 315, 925-one 930). The method takes a compound 1 and hydrazine hydrate in the literature as raw materials, and compounds 9a (namely the compound V of the invention) are obtained by condensation and dehydration. The method has low selectivity of reaction due to tautomerism of the compound 1. In addition, according to the literature (European Journal of Medicinal chemistry, 2015, 102, 310-319), it is reported that the synthesis of the starting compound 1 needs to be carried out under high temperature (200 ℃), which is not only dangerous to operate but also low in yield (27%).

Disclosure of Invention

The purpose of the invention is as follows: aiming at the defects in the prior art, the invention provides a method for preparing a compound V with high selectivity, which has the advantages of mild condition, simple operation and high purity of the obtained product.

A preparation method of an olaparide impurity compound VI is characterized by comprising the following steps:

firstly, adding a compound I, a compound II and a solvent into a reaction bottle, stirring, adding alkali, heating to a certain temperature, and reacting to obtain a compound III.

And secondly, adding the compound III and a solvent into a reaction bottle, adding hydrazine hydrate, heating to a certain temperature, and carrying out heat preservation reaction until the reaction end point to obtain a compound IV.

And thirdly, adding the compound IV, a solvent and a catalyst into a reaction kettle, stirring, heating to a certain temperature, adding thionyl chloride, keeping the temperature to react to the end point, cooling to 0-20 ℃, and adding alkali to finally obtain a compound V.

Expressed by the reaction formula:

specifically, the solvent in the first step is an organic solvent or water, and the organic solvent may be one or more of acetonitrile, THF, DMF or DMSO. The base is organic amine or inorganic base, the organic amine comprises triethylamine, pyridine, 4-methylpyridine, diisopropylethylamine or N, N-Dimethylaminopyridine (DMAP), the inorganic base comprises alkali metal hydroxide and alkali metal carbonate (such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate), the inorganic base is preferred, the alkali metal carbonate is more preferred, and the sodium bicarbonate is most preferred. The reaction of this step may be carried out at a temperature of from 0 to 100 ℃ and preferably from 30 to 45 ℃.

Specifically, the solvent in the second step may be an organic solvent or water, preferably an organic solvent, more preferably acetonitrile, THF, and most preferably THF. The reaction of this step is preferably carried out at 50 to 100 ℃ and more preferably at 60 to 80 ℃.

Specifically, the solvent in the third step is an organic solvent, preferably toluene, xylene, dichloromethane, chloroform, or the like, and more preferably toluene. The catalyst is DMF, N-Dimethylaminopyridine (DMAP) or pyridine, and is preferably DMAP. The base may be organic base such as triethylamine, pyridine, 4-methylpyridine, diisopropylethylamine or N, N-dimethylaminopyridine (DMAP for short), or inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, and triethylamine is most preferable. The reaction of this step is preferably carried out at 60 to 100 ℃ and more preferably at 75 to 85 ℃.

Has the advantages that: the preparation method of the compound V provided by the invention has high selectivity, the raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild, and the purity of the obtained compound V can reach more than 99% without adopting column chromatography purification.

Detailed Description

The present invention is further illustrated by the following examples, but the invention is not limited to the scope of the claims.

EXAMPLE 1 preparation of Compound III

Adding 100.0g of compound into a 1L three-necked bottleCompound I, 58.9g of Compound II, 1200mL of water, was stirred and the temperature was raised to about 30 ℃. An aqueous solution of 442g of sodium hydrogencarbonate (42 g of sodium hydrogencarbonate dissolved in 400g of water) was added dropwise thereto, and the reaction system was further heated to about 45 ℃. After the reaction is finished, solid is separated out, the solid is filtered, a filter cake is dissolved in a certain amount of sodium bicarbonate aqueous solution (the pH of the mixture solution is controlled to be about 13), the aqueous solution is extracted for 2 times by dichloromethane, the pH of an aqueous phase is adjusted to be 2 by hydrochloric acid, white solid is separated out, the white solid is filtered, the filter cake is dried, and the compound III is obtained, and the HPLC purity of the product is 99.82%. M/z [ M ]]⁺：267.03。

EXAMPLE 2 preparation of Compound IV

A250 mL three-necked flask was charged with 45g of wet compound III (0.15 mol) and 180mL of THF, stirred, and 7.0g of 85% hydrazine hydrate was added dropwise, and the mixture was heated to 65-70 ℃ for reaction overnight. The reaction was complete by TLC. Cooling and filtering to obtain white solid. The white solid was dissolved in 7.2g aqueous sodium hydroxide solution and extracted 2 times with dichloromethane, and the aqueous phase was adjusted to pH 4-5 to precipitate a white solid. Filtering, pulping and washing the filter cake with ethanol at 65-70 ℃, filtering, and drying to obtain 37.8g of white solid.¹HNMR（DMSO-D6，400MHz）：δppm12.71 (brs，0.77H)，12.4 (s，1H)，8.28-8.27 (d，1H)，8.04-8.02 (d，1H)，7.91(t，2H)，7.86-7.85（d，1H），7.48-7.46（t，1H），7.37-7.35（d，1H），7.30-7.28（d，1H），4.70（s，2H）。m/z[M-H]^-：279.17。

EXAMPLE 3 preparation of Compound V

Adding 5.0g of compound IV, 26g of toluene and 0.21g of DMAP into a 250mL four-mouth bottle, stirring, heating the reaction system to 75 ℃, dropwise adding 2.4g of thionyl chloride, keeping the temperature for reaction for 5-6h after the dropwise adding is finished, and monitoring the reaction by TLC. Temperature reductionAnd (3) dropwise adding 8.0g of triethylamine at 0-20 ℃, stirring for 1-2 hours, adding 30mL of water, pulping, filtering, leaching a filter cake with a small amount of water, and drying to obtain 4.5g of yellow solid with the HPLC purity of 99.18%.¹HNMR（DMSO-D6，400MHz）：δppm11.59-11.55(dd,1H)，8.52(d,1H)，8.35(d,1H)，8.23(d,1H)，8.02(s,1H)，7.91 (d,1H)，7.84(d,2H)，7.759（s，1H），7.64（t，1H）。m/z[M +H]⁺：263.16，m/z[M -H]^-：261.12。

EXAMPLE 4 preparation of Compound V

Adding 5.0g of compound IV, 26g of toluene and 0.14g of DMF (dimethyl formamide) into a 250mL four-neck flask, stirring, heating the reaction system to 80 ℃, dropwise adding 2.0g of thionyl chloride, keeping the temperature for reaction for 5-6h after the dropwise adding is finished, and monitoring the reaction by TLC. Cooling to 0-20 ℃, dropwise adding 8.0g of triethylamine, stirring for 1-2 hours, adding 30mL of water, pulping, filtering, leaching a filter cake with a small amount of water, and drying to obtain a yellow solid with the HPLC purity of 99.5%.

EXAMPLE 5 preparation of Compound V

Adding 5.0g of compound IV, 30g of toluene and 0.15g of pyridine into a 250mL four-mouth bottle, stirring, heating the reaction system to 85 ℃, dropwise adding 2.5g of thionyl chloride, keeping the temperature for reaction for 5-6h after the dropwise adding is finished, and monitoring the reaction by TLC. Cooling to 0-20 ℃, dropwise adding 8.0g of triethylamine, stirring for 1-2 hours, adding 30mL of water, pulping, filtering, leaching a filter cake with a small amount of water, and drying to obtain a yellow solid with the HPLC purity of 99.2%.

The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.

Claims

1. A process for the preparation of olapari impurity compound V, characterized in that it comprises the steps of:

firstly, adding a compound I, a compound II and a solvent into a reaction bottle, stirring, adding alkali, heating to a certain temperature, and reacting to obtain a compound III;

secondly, adding the compound III and a solvent into a reaction bottle, adding hydrazine hydrate, heating to a certain temperature, and carrying out heat preservation reaction to the end point of the reaction to obtain a compound IV;

thirdly, adding the compound IV, a solvent and a catalyst into a reaction kettle, stirring, heating to a certain temperature, adding thionyl chloride, keeping the temperature to react to a terminal point, cooling to 0-20 ℃, and adding alkali to finally obtain a compound V; the catalyst is DMF, DMAP or pyridine;

expressed by the reaction formula:

。

2. the method according to claim 1, wherein the solvent in the first step is one or more of acetonitrile, tetrahydrofuran, DMF, DMSO or water; the alkali is organic amine or inorganic alkali; the temperature is 0-100 ℃.

3. The method according to claim 2, wherein the solvent in the first step is water; the alkali is inorganic alkali; the temperature is 30-45 ℃.

4. The process of claim 3, wherein the inorganic base is sodium bicarbonate.

5. The method of claim 1, wherein the solvent in the second step is one or more of acetonitrile, water or THF; the temperature is 50-100 ℃.

6. The method of claim 5, wherein the solvent in the second step is THF; the temperature is 60-80 ℃.

7. The method of claim 1, wherein the solvent in the third step is toluene, xylene, dichloromethane or chloroform; the alkali is triethylamine, diisopropylethylamine or sodium bicarbonate; the temperature is 60-100 ℃.

8. The method of claim 7, wherein the solvent in the third step is toluene; the alkali is triethylamine; the temperature is 75-85 ℃.