Intermediates of talazoparib and methods of making and uses thereof

Abstract

The application provides a novel preparation method and intermediate for preparing talabostat. The preparation method is simple in process, easy to operate, mild in conditions, low in side reactions, friendly to the environment, low in cost, good in product quality and suitable for industrialized production.

Description

Technical Field

[0001] This invention relates to an intermediate of talazoparib, its preparation method, and its uses. Background Technology

[0002] Talazoparib, chemical name: (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one-4-methylbenzenesulfonate; molecular formula: C 19 H 14 F2N6O.C7H8O3S. Approved in the United States in October 2018 under the brand name Talzenna, for the treatment of HER2-negative locally advanced or metastatic breast cancer with harmful or suspected BRAC mutations. Its chemical structure is shown in Formula I:

[0003]

[0004] Most methods in the art for preparing tapolarib or its salts employ the intermediate (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (e.g., CN102834008A, WO2015069851A1, WO2018205938A1, etc.), as shown below.

[0005]

[0006] This synthesis process has many drawbacks, such as: the reaction requires an excessive amount of acetic anhydride, which causes significant environmental pollution; the aldehydes used as raw materials have low boiling points and often contain a lot of low-boiling-point solvents (such as DCM and THF), which makes it difficult to reach the required reaction temperature and increases side reactions; the reaction needs to be carried out at a high temperature, which increases energy consumption and costs. Summary of the Invention

[0007] This invention provides a novel method for preparing tprazole and an intermediate. The method described in this invention is simple, easy to operate, operates under mild conditions, has few side reactions, is environmentally friendly, has low cost, and produces high-quality products, making it more suitable for industrial production.

[0008] A first aspect of the present invention provides a method for preparing (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (compound of formula B), comprising the following steps:

[0009] Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction under the action of a base to obtain compound A;

[0010] Step b: Under alkaline conditions, compound A undergoes an elimination reaction in the presence of a dehydrating agent to yield compound B.

[0011]

[0012] In step a,

[0013] In some embodiments, the base in the condensation reaction is selected from organic or inorganic bases; preferably, it is selected from one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA, DBU, LDA, lithium amino, lithium hydride, lithium di(trimethylsilyl)amino, and pyridine; more preferably, it is selected from one or more of TEA, pyridine, sodium carbonate, potassium carbonate, and cesium carbonate; and even more preferably, it is TEA.

[0014] In some embodiments, the solvent used in the condensation reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, methyl tert-butyl ether, methyl cyclopentyl ether, 1,4-dioxane, methanol, and acetonitrile; tetrahydrofuran is preferred.

[0015] In some embodiments, the condensation reaction is carried out at a temperature of 10-60°C, preferably at room temperature;

[0016] In some embodiments, the condensation reaction takes 4-20 hours, preferably 8-12 hours;

[0017] In some embodiments, the molar ratio of compound 2 and base in the condensation reaction is 1:1 to 1:2.5, preferably 1:1 to 1:2;

[0018] In some embodiments, the base in the condensation reaction is selected from organic bases; the temperature of the condensation reaction is 10-60°C;

[0019] In some embodiments, the condensation reaction further includes a post-processing step.

[0020] In step b,

[0021] In some embodiments, the dehydrating agent in the elimination reaction is selected from one or more of acetic acid, acetic anhydride, methanesulfonic anhydride, propylphosphonic anhydride, acetyl chloride, thionyl chloride, p-toluenesulfonyl chloride, or phosphorus oxychloride; preferably acetic anhydride;

[0022] In some embodiments, the solvent used in the elimination reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, 1,4-dioxane, or acetonitrile; tetrahydrofuran is preferred.

[0023] In some embodiments, the base in the elimination reaction is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA, and DBU; preferably TEA;

[0024] In some embodiments, the elimination reaction is carried out at room temperature;

[0025] In some embodiments, the base in the elimination reaction is selected from organic bases; the dehydrating agent is selected from acetic anhydride;

[0026] In some embodiments, the molar ratio of compound A to base in the elimination reaction is 1:1 to 1:4; preferably 1:1 to 1:3.

[0027] In some implementations, the elimination reaction further includes a post-processing step.

[0028] In some embodiments, the method for preparing compound B includes the following steps:

[0029] Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction at 10-60℃ under the action of an organic base to obtain compound A;

[0030] Step b: Under organic base conditions, compound A undergoes an elimination reaction in the presence of acetic anhydride to yield compound B.

[0031] In some embodiments, the method for preparing compound B includes the following steps:

[0032] Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction at 10-60℃ under the action of TEA to obtain compound A;

[0033] Step b: Under TEA conditions, compound A undergoes an elimination reaction in the presence of an equivalent amount of acetic anhydride to yield compound B.

[0034] In another aspect of the present invention, a compound of formula A is provided.

[0035]

[0036] In another aspect of the invention, the use of compound A in the preparation of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (compound B) is provided.

[0037] In another aspect of the invention, the use of compound A in the preparation of tprazole or a salt thereof is provided.

[0038] In some embodiments, the salt is a methanesulfonate.

[0039] In another aspect, the present invention provides a method for preparing tapolaparib or a salt thereof, comprising any of the above preparation methods.

[0040] In some embodiments, the salt is a methanesulfonate.

[0041] The beneficial effects of this invention are as follows:

[0042] (1) This invention provides a novel method for preparing tapolaparib and an intermediate;

[0043] (2) The preparation method of the key intermediate (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (compound B) of the present invention adopts a novel process. The preparation method is simple, easy to operate, mild, has few side reactions, is environmentally friendly, low in cost, and produces high-quality products, making it more suitable for industrial production.

[0044] (3) The preparation method of the present invention uses an equivalent amount of acetic anhydride in the elimination reaction step, which avoids the use of existing technology to eliminate excess acetic anhydride in the reaction, saves raw materials, and reduces the treatment cost of waste acid. Detailed Implementation

[0045] abbreviation

[0046]

[0047]

[0048] definition

[0049] To facilitate understanding of the disclosure described in this application, some terms are defined as follows. Generally, the nomenclature used in this application and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used in this application generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0050] The following are exemplary embodiments of how to prepare and test the compounds. Although the examples are only illustrative of some implementations, it should be understood that the following examples are exemplary and not limiting.

[0051] Example 1

[0052]

[0053] 31.1 g of 1-methyl-1H-1,2,4-triazol-5-carboxaldehyde (compound of formula 1), 49.7 g of 6-fluoro-4-nitrobenzisofuran-1-(3H)-one (compound of formula 2), 350 ml of THF, and 50 ml of TEA were added to a 2 L four-necked flask, stirred at room temperature for 10 h, filtered, and dried under vacuum to obtain 66.1 g of off-white powder of compound A, with a yield of 85.1%.

[0054] ESI-MS (m / z) 309.2 [M+H]+.

[0055] 1 H NMR (400MHz, DMSO-d6): δ3.93(s,3H), δ5.64-5.66(d,J=6.8Hz,1H), δ6.11-6.13(d,J=7.2Hz,1H), δ6.53 (s,1H), δ7.94(s,1H), δ8.34-8.36q, J1=2.4Hz, J2=6.6Hz, 1H), δ8.62-8.65q, J1=2.0Hz, J2=8.8Hz, 1H).

[0056] Example 2

[0057]

[0058] 25.0 g of compound A was added to a 1 L three-necked flask. After purging with nitrogen three times, 125 ml of THF, 22.5 ml of anhydrous TEA, and 7.5 ml of acetic anhydride were added. The reaction system was a white suspension, which was stirred overnight at room temperature. As the reaction proceeded, the color gradually turned orange. The reaction was monitored by TLC (DCM:EA = 1:1). After compound A had reacted completely, the mixture was filtered. The filter cake was washed twice with 37.5 ml of water and once with 30 ml of EA. The filter cake was collected and dried in a forced-air drying oven to obtain 17.2 g of compound B, with a yield of 73.1%, as a pale yellow powder.

[0059] It should be noted that the above embodiments are merely illustrative of the concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They do not limit the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (compound B), characterized in that, It includes the following steps: Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction under the action of a base to obtain compound A; Step b: Under alkaline conditions, compound A undergoes an elimination reaction in the presence of a dehydrating agent to yield compound B.

2. The preparation method according to claim 1, characterized in that, Step a satisfies one or more of the following conditions: (1) The base in the condensation reaction is selected from organic or inorganic bases; preferably, it is selected from one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA, DBU, LDA, lithium amino, lithium hydride, lithium di(trimethylsilyl)amino, and pyridine. (2) The solvent used in the condensation reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, methyl tert-butyl ether, methyl cyclopentyl ether, 1,4-dioxane, methanol, and acetonitrile; (3) The temperature of the condensation reaction is 10-60℃; (4) The condensation reaction takes 4-20 hours; (5) The molar ratio of compound 2 and base in the condensation reaction is 1:1 to 1:2.5; (6) The base in the condensation reaction is selected from organic bases; the temperature of the condensation reaction is 10-60℃; (7) The condensation reaction also includes a post-processing step.

3. The preparation method according to any one of claims 1-2, characterized in that, Step b satisfies one or more of the following conditions: (1) The dehydrating agent in the elimination reaction is selected from one or more of acetic acid, acetic anhydride, methanesulfonic anhydride, propylphosphonic anhydride, acetyl chloride, thionyl chloride, p-toluenesulfonyl chloride or phosphorus oxychloride; (2) The solvent used in the elimination reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, 1,4-dioxane or acetonitrile; (3) The base in the elimination reaction is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA, and DBU; (4) The elimination reaction is carried out at room temperature; (5) In the elimination reaction, the base is selected from organic bases; the dehydrating agent is selected from acetic anhydride; (6) In the elimination reaction, the molar ratio of compound A to base is 1:1 to 1:4; (7) The elimination reaction also includes a post-treatment step.

4. The preparation method according to claim 1, characterized in that, Includes the following steps; Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction at 10-60℃ under the action of an organic base to obtain compound A; Step b: Under organic base conditions, compound A undergoes an elimination reaction in the presence of acetic anhydride to yield compound B.

5. The preparation method according to claim 4, characterized in that, Includes the following steps; Step a: Compounds of Formula 1 and Formula 2 undergo a condensation reaction at 10-60℃ under the action of TEA to obtain compound A; Step b: Under TEA conditions, compound A undergoes an elimination reaction in the presence of an equivalent amount of acetic anhydride to yield compound B.

6. Use of compound A in the preparation of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitrobenzisofuran-1-(3H)-one (compound B), 7. Use of compound A in the preparation of tapolarib or its salts.

8. A method for preparing tapolarib or a salt thereof, comprising the preparation method as described in any one of claims 1-5.

Images