Preparation method of olaparib intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an olaparib intermediate. According to the method, SM-1 and SM-2 are used as raw materials, the target compound I is directly prepared through reaction, synthesis steps are short, reaction is rapid, operation is easy and convenient, and operations such as slow dropwise adding and cooling are not needed; and various problems caused by instability of the material when the aldehyde group material is used for reaction in the prior art can be effectively avoided, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an olaparib intermediate. Background Art

[0002] Olaparib is a poly (ADP ribose) polymerase (PARP) inhibitor and the world's first PARP inhibitor drug to be marketed. Olaparib was first developed by KuDOS in the UK. In December 2005, AstraZeneca acquired KuDOS and obtained its development rights. The trade name is Lynparza. It was approved for marketing in the EU on December 16, 2014, and was approved for marketing by the US FDA on December 19 of the same year. It is used to treat advanced ovarian cancer with BRCA1 / 2 gene mutations. It has significant efficacy, few adverse reactions, and good short-term tolerance in patients. On August 17, 2017, the US FDA approved the marketing of 100mg and 150mg olaparib tablets for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. On January 12, 2018, the FDA approved olaparib tablets for use in patients with breast cancer with gBRCA mutations. On September 20, 2018, the National Medical Products Administration (NMPA) approved the marketing of 100mg and 150mg Olaparib tablets in China. Its chemical structure is shown below:

[0003]

[0004] There are many reports on the synthesis methods of Olaparib in the prior art, including patents CN1788000B, CN101528714A and literature J.Med.Chem., 2008, 51(20): 6581-6591, J.Med.Chem., 2015, 58(21): 8683-8693, and Improved Synthesis Process of Olaparib, Journal of Huaqiao University (Natural Science Edition), 2017, 38(4): 521-524. 3-Hydroxyphthalide is used as the starting material, which is first reacted with dimethyl phosphite; then reacted with 3-cyano-4-fluorobenzaldehyde through Wittig-Horner reaction to obtain 2-fluoro-5-[(E / Z)-(3-oxo-3H-isobenzofuran-1-ylmethylene)]benzonitrile (I-1). Compound I-1 is hydrolyzed under alkaline conditions and cyclized with hydrazine hydrate to obtain the key intermediate of Olaparib, 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid. The synthetic route is as follows:

[0005]

[0006] Patent CN112979557A also uses o-carboxybenzaldehyde as the starting material, first reacts with dimethyl phosphite, and then reacts with 3-cyano-4-fluorobenzaldehyde through Wittig-Horner reaction to generate compound I-1. The difference from the above route is that the lactone is first hydrazinolyzed, and then the nitrile group is further hydrolyzed in a "one-pot" reaction to obtain 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid. The synthetic route is as follows:

[0007]

[0008] However, the above routes all involve a "one-pot" reaction of hydrolysis of cyano group to carboxyl group and cyclization with hydrazine hydrate. In the actual preparation process, there will be by-products of incomplete cyano hydrolysis and incomplete hydrazine hydrate cyclization, with low yield and purity, which is not conducive to the preparation and clinical application of Olaparib drugs.

[0009] Patent CN105085408A uses 2-fluoro-5-formylbenzoic acid instead of 3-nitrile-4-fluorobenzaldehyde to react with (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dialkyl ester to obtain 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoic acid (I-2), which is then degraded with hydrazine hydrate to prepare the key intermediate of olaparib, 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid. The synthesis route is as follows:

[0010]

[0011] Patent CN110790710A uses o-carboxybenzaldehyde as the starting material, reacts with dimethyl phosphite to generate (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphonate, and then uses 2-fluoro-5-formylbenzoic acid instead of 3-nitrile-4-fluorobenzaldehyde for the reaction. This reaction combines the Wittig-Horner reaction with the hydrazine hydrate hydrazinolysis reaction in a "one-pot method" to prepare the key intermediate of Olaparib, 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid, which not only omits the cyano hydrolysis operation, but also simplifies other complex unit operations, shortening the reaction route and reaction time. The synthesis route is as follows:

[0012]

[0013] Patent CN105085407A is to react 2-fluoro-5-formylbenzoic acid with 1-substituted piperazine to generate 3-(4-substituted)piperazine-1-carbonyl)-4-fluorobenzaldehyde, i.e. 3-(4-tert-butyloxycarbonylpiperazine-1-ylformyl)-4-fluorobenzaldehyde or 3-[(4-cyclopropylformyl)piperazine-1-ylformyl]-4-fluorobenzaldehyde, and then react with (3-oxo-1,3-dihydro-isobenzofuran-1-yl) dialkyl phosphate to obtain 1-substituted-4-[5-(3-oxo-3H-isobenzofuran-1-ylmethylene)-2-fluorobenzaldehyde. [benzoyl] piperazine, i.e., 1-(tert-butyloxycarbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-ylmethylene)-2-fluorobenzoyl] piperazine (I-3) or 1-(cyclopropylformyl)-4-[5-(3-oxo-3H-isobenzofuran-1-ylmethylene)-2-fluorobenzoyl] piperazine (I-4), and finally reacted with hydrazine hydrate to obtain the intermediate 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]-1-tert-butyloxycarbonyl piperazine (R1=BOC) or olaparib (R1=cyclopropylformyl). The synthetic route is as follows:

[0014]

[0015] Patent CN103717609A uses 3-bromo-4-fluorobenzaldehyde as the starting material, reacts with (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphonate to obtain 3-(3-bromo-4-fluorophenylmethylene)-3H-isobenzofuran-1-one (I-5), and then cyclizes with hydrazine hydrate to obtain 4-(3-bromo-4-fluorobenzyl)-2H-phthalazin-1-one. Then, according to the method of J.Am.Chem.Soc., 2014, 45(42):6142-6147, the target product Olaparib is obtained by carbonylation coupling.

[0016]

[0017] However, the above processes all use aldehyde compounds, namely 3-cyano-4-fluorobenzaldehyde, 2-fluoro-5-formylbenzoic acid and 3-bromo-4-fluorobenzaldehyde as raw materials for Wittig-Horner reaction, but the aldehyde compounds themselves are unstable and have reducing properties, and are easily oxidized to carboxylic acids, so that the key intermediate I of Olaparib obtained by the reaction contains related substance impurities, and the reaction process requires inert gas protection and control of anhydrous reaction conditions, which is complicated. The chemical structure of the relevant aldehyde material is shown below:

[0018]

[0019] In summary, given the above-mentioned shortcomings in the preparation method of the key intermediate I of Olaparib in the above-mentioned process, it is still a problem to be solved to study and find a reaction route suitable for industrial production of Olaparib or its key intermediates with mild reaction conditions, simple operation process, high product yield and high purity. Summary of the invention

[0020] The present invention provides a novel method for preparing an olaparib key intermediate I. The target product prepared by the method has high purity and yield, mild reaction conditions, safer operation, and is suitable for industrialized scale-up production.

[0021] The specific technical solutions of the present invention are as follows:

[0022] A method for preparing an olaparib intermediate comprises the following steps:

[0023] Add alkali, SM-1 and SM-2 to an organic solvent, control the temperature and react. After the reaction is completed, post-treatment is performed to obtain compound I. The reaction formula is as follows:

[0024]

[0025] The chemical structures of relevant materials and products are as follows:

[0026]

[0027] Preferably, the base is one of t-BuOK and t-BuONa.

[0028] Preferably, the organic solvent is one of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof, preferably tetrahydrofuran or 2-methyltetrahydrofuran.

[0029] Preferably, the molar ratio of the compound SM-1 to the compound SM-2 and the base is 1:1.05-1.7:1.5-2.5, preferably 1:1.1:2.0.

[0030] Preferably, the reaction temperature is 25-50°C, preferably 40-45°C.

[0031] In a preferred embodiment, when R1=Me or Et; R2=CN, or Br, the post-treatment step is: diluting the reaction solution with an appropriate amount of water, extracting with an organic solvent, combining the organic phases, concentrating to dryness under reduced pressure, and recrystallizing the concentrate to obtain compound I. Preferably, the organic solvent for extraction is one of dichloromethane, chloroform and ethyl acetate.

[0032] In a preferred embodiment, when R1=Me or Et; R2=COOH, the post-treatment step is: diluting the reaction solution with an appropriate amount of water, adjusting the pH to 3-4 with dilute hydrochloric acid, filtering, drying the filter cake, and recrystallizing to obtain compound I.

[0033] Preferably, the recrystallization solvent is n-hexane / ethyl acetate or n-hexane / methyl tert-butyl ether, wherein the volume ratio of n-hexane to ethyl acetate or methyl tert-butyl ether is 1-2:1.

[0034] Beneficial effects of the present invention:

[0035] The present invention provides a method for preparing a key intermediate I of Olaparib, wherein SM-1 and SM-2 are used as starting materials, and the two react to directly prepare a target compound I, and the synthesis steps are short, the reaction is rapid, the operation is simple, and there is no need for slow dripping, cooling and other operations. The present invention uses an alcohol-based material SM-2 for reaction, which can effectively solve the various problems caused by the instability of the material itself when the prior art uses an aldehyde-based material for reaction. The preparation process of the key intermediate I of Olaparib of the present invention has mild reaction conditions, simple post-processing operation, and the obtained product has a high yield and purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0036] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0037] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0038] Preparation of 2-fluoro-5-[(E / Z)-(3-oxo-3H-isobenzofuran-1-ylmethylene)]benzonitrile (I-1):

[0039]

[0040] Example 1

[0041] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-1 (16.63 g, 0.11 mol) were added to tetrahydrofuran (250 ml), the temperature was raised to 35-40 ° C and the reaction was carried out for about 30 minutes. After the reaction was completed, the reaction solution was diluted with 2500 ml of water, extracted with dichloromethane (300 ml × 3), the organic phases were combined, washed with saturated brine (200 ml), and concentrated to dryness under reduced pressure. The concentrate was recrystallized from n-hexane / ethyl acetate to obtain compound I-1 with a yield of 98.8% and a purity of 99.82%.

[0042] Example 2

[0043] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-1 (25.70 g, 0.17 mol) were added to tetrahydrofuran (300 ml), the temperature was raised to 25-30 ° C and the reaction was carried out for about 50 minutes. After the reaction was completed, the reaction solution was diluted with 2500 ml of water, extracted with dichloromethane (300 ml × 3), the organic phases were combined, washed with saturated brine (200 ml), and concentrated to dryness under reduced pressure. The concentrate was recrystallized from n-hexane / ethyl acetate to obtain compound I-1 with a yield of 98.0% and a purity of 99.43%.

[0044] Example 3

[0045] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-1 (15.87 g, 0.105 mol) were added to tetrahydrofuran (250 ml), the temperature was raised to 25-30 ° C and the reaction was carried out for about 50 minutes. After the reaction was detected to be completed, the reaction solution was diluted with 2500 ml of water, extracted with dichloromethane (300 ml × 3), the organic phases were combined, washed with saturated brine (200 ml), and concentrated to dryness under reduced pressure. The concentrate was recrystallized from n-hexane / ethyl acetate to obtain compound I-1 with a yield of 97.3% and a purity of 99.67%.

[0046] Preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoic acid (I-2)

[0047]

[0048] Example 4

[0049] t-BuOK (22.44 g, 0.2 mol), SM-1-2 (R = Et, 27.02 g, 0.1 mol), and SM-2-2 (18.72 g, 0.11 mol) were added to 1,4-dioxane (280 ml), and the temperature was raised to 35-40 ° C. and the reaction was carried out for about 30 minutes. After the reaction was completed, the reaction solution was diluted with 2000 ml of water, and the pH was adjusted to about 3 with 1 mol / L hydrochloric acid. The filter cake was dried under reduced pressure and recrystallized from n-hexane / ethyl acetate to obtain compound I-2 with a yield of 98.2% and a purity of 99.70%.

[0050] Example 5

[0051] t-BuOK (28.05 g, 0.25 mol), SM-1-2 (R = Et, 27.02 g, 0.1 mol), and SM-2-2 (18.72 g, 0.11 mol) were added to 1,4-dioxane (280 ml), and the temperature was raised to 45-50 ° C. and the reaction was carried out for about 30 minutes. After the reaction was completed, the reaction solution was diluted with 2000 ml of water, and the pH was adjusted to about 3 with 1 mol / L hydrochloric acid. The filter cake was filtered and dried under reduced pressure, and then recrystallized from n-hexane / ethyl acetate to obtain compound I-2 with a yield of 97.9% and a purity of 99.51%.

[0052] Example 6

[0053] t-BuOK (16.83 g, 0.15 mol), SM-1-2 (R = Et, 27.02 g, 0.1 mol), and SM-2-2 (18.72 g, 0.11 mol) were added to tetrahydrofuran (280 ml), and the temperature was raised to 45-50 ° C. and the reaction was carried out for about 30 minutes. After the reaction was completed, the reaction solution was diluted with 2000 ml of water, and the pH was adjusted to about 3 with 1 mol / L hydrochloric acid. The filter cake was dried under reduced pressure and recrystallized from n-hexane / ethyl acetate to obtain compound I-2 with a yield of 97.1% and a purity of 99.33%.

[0054] Preparation of 1-(tert-butyloxycarbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-ylmethylene)-2-fluorobenzoyl]piperazine (I-3)

[0055]

[0056] Example 7

[0057] t-BuONa (19.22 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-3 (37.22 g, 0.11 mol) were added to tetrahydrofuran (350 ml), the temperature was raised to 35-40 ° C and the reaction was carried out for about 45 minutes. After the reaction was completed, the reaction solution was diluted with 3500 ml of water, extracted with dichloromethane (500 ml × 3), the organic phases were combined, washed with saturated brine (400 ml), concentrated to dryness under reduced pressure, and recrystallized from n-hexane / ethyl acetate to obtain compound I-3 with a yield of 98.3% and a purity of 99.74%.

[0058] Example 8

[0059] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-3 (37.22 g, 0.11 mol) were added to toluene (350 ml), the temperature was raised to 35-40 ° C and the reaction was carried out for about 45 minutes. After the reaction was completed, the reaction solution was diluted with 3500 ml of water, extracted with dichloromethane (500 ml × 3), the organic phases were combined, washed with saturated brine (400 ml), concentrated to dryness under reduced pressure, and recrystallized from n-hexane / methyl tert-butyl ether to obtain compound I-3 with a yield of 98.0% and a purity of 99.59%.

[0060] Preparation of 1-(cyclopropylcarbonyl)-4-[5-(3-oxo-3H-isobenzofuran-1-ylmethylene)-2-fluorobenzoyl]piperazine (I-4)

[0061]

[0062] Example 9

[0063] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-4 (33.70 g, 0.11 mol) were added to 2-methyltetrahydrofuran (350 ml), the temperature was raised to 35-40 ° C and the reaction was carried out for about 45 minutes. After the reaction was completed, the reaction solution was diluted with 3500 ml of water, extracted with chloroform (400 ml × 3), the organic phases were combined, washed with saturated brine (400 ml), concentrated to dryness under reduced pressure, and recrystallized from n-hexane / ethyl acetate to obtain compound I-4 with a yield of 97.8% and a purity of 99.64%.

[0064] Preparation of 3-(3-bromo-4-fluorophenylmethylene)-3H-isobenzofuran-1-one (I-5)

[0065]

[0066] Example 10

[0067] t-BuOK (22.44 g, 0.2 mol), SM-1-1 (R = Me, 24.22 g, 0.1 mol), SM-2-5 (22.55 g, 0.11 mol) were added to tetrahydrofuran (270 ml), the temperature was raised to 35-40 ° C and the reaction was carried out for about 30 minutes. After the reaction was completed, the reaction solution was diluted with 2700 ml of water, extracted with ethyl acetate (400 ml × 3), the organic phases were combined, washed with saturated brine (300 ml), concentrated to dryness under reduced pressure, and recrystallized from n-hexane / ethyl acetate to obtain compound I-5 with a yield of 98.6% and a purity of 99.75%.

[0068] Embodiment 11

[0069] SM-1-1 (15.0 g, 0.062 mol) was dissolved in THF (120 mL), 3-bromo-4-fluorobenzaldehyde (11.4 g, 0.056 mol) was added, and the mixture was stirred at 30 ° C for about 1 hour, and the mixture was dissolved. The temperature was controlled at 30 ° C, and a tetrahydrofuran solution of sodium tert-butoxide (8.1 g, 0.084 mol) was added dropwise. Heat was released during the addition and a large amount of solid was precipitated. The temperature was controlled at 30 ° C. After reacting for 10 hours, the reaction was detected to be complete. The solvent was removed by concentration under reduced pressure, 95% ethanol (600 ml) was added, and the mixture was stirred for 4 hours at 30 ° C. Compound I-5 was obtained by filtration with a yield of 80.2% and a purity of 97.38%.

Claims

1. A method for preparing an olaparib intermediate, comprising the following operations: adding a base, SM-1, and SM-2 to an organic solvent, reacting at a controlled temperature, and after detecting that the reaction is complete, post-treating to obtain compound I, the reaction formula is as follows: wherein R1 = Me or Et; R2 = CN, COOH, or Br.

2. The preparation method according to claim 1, characterized in that: The base is one of t-BuOK and t-BuONa.

3. The preparation method according to claim 1, characterized in that: The organic solvent is one of 1,4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof, preferably tetrahydrofuran or 2-methyltetrahydrofuran.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound SM-1 to the compound SM-2 and the base is 1:1.05-1.7:1.5-2.5, preferably 1:1.1:2.

0.

5. The preparation method according to claim 1, characterized in that: The reaction temperature is 25-50°C, preferably 40-45°C.

6. The preparation method according to claim 1, characterized in that: When R1=Me or Et;R2=CN, or Br, the post-treatment step is: diluting the reaction solution with an appropriate amount of water, extracting with an organic solvent, combining the organic phases, concentrating to dryness under reduced pressure, and recrystallizing the concentrate to obtain compound I.

7. The preparation method according to claim 1, characterized in that: When R1=Me or Et; R2=COOH, the post-treatment step is: diluting the reaction solution with an appropriate amount of water, adjusting the pH to 3-4 with dilute hydrochloric acid, filtering, drying the filter cake, and recrystallizing to obtain compound I.

Images