Preparation method of olaparil intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of olaparib intermediate 2-fluoro-5-[(4-carbonyl-3, 4-dihydrophthalazine-1-yl) methyl] methyl (ethyl) benzoate (I). According to the method, SM-1 and SM-2 are taken as raw materials, the target compound I is directly prepared through dehalogenation coupling under nickel catalysis, synthesis steps are short, operation is safe, simple and convenient, and amplification is easy; the target product can be prepared with high yield and high purity, 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. PARP inhibitors represent a new class of anti-cancer treatments that work by exploiting DNA repair defects in BRCA-mutated cancer cells and inducing cell death. Olaparib is the world's first PARP inhibitor drug to be marketed, used to treat ovarian cancer, breast cancer, pancreatic cancer and prostate cancer. Its chemical structure is shown below:

[0003]

[0004] Currently, there are many reports on the synthesis methods of Olaparib, among which there are many schemes for preparing Olaparib or its intermediates by coupling reaction.

[0005] For example, patent CN105820126B and document "New Synthesis of Olaparib", Chinese Journal of Pharmaceutical Industry, 2016, 47(8):996-998, 5-(bromomethyl)-2-fluorobenzoic acid methyl ester is used as a raw material, and a borylation reaction is carried out with catechol borane to obtain (4-fluoro-3-(methoxycarbonyl)benzyl)boric acid, which is then reacted with 4-(chloromethyl)phthalazin-1(2H)-one to produce 2-fluoro-5-(4-oxo-3,4-dihydronaphthoazin-1-yl)methyl)benzoic acid methyl ester by Suzuki coupling reaction, followed by alkaline hydrolysis to obtain 2-fluoro-5-((4-oxo-3,4-dihydronaphthoazin-1-yl)methyl)benzoic acid, and finally reacted with cyclopropyl(piperazin-1-yl)methyl ketone hydrochloride under the action of N,N′-carbonyldiimidazole (CDI) to obtain Olaparib. The reaction route is as follows:

[0006]

[0007] Patent CN113234024A uses 4-methylphthalazin-1(2H)-one as the starting material, and reacts with NBS and AIBN to obtain 4-(bromomethyl)phthalazin-1(2H)-one through bromination reaction, and then undergoes Suzuki coupling reaction with (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid under the action of catalyst and base to produce 2-fluoro-5-((4-oxo-3,4-phthalazin-1-yl)methyl)benzoic acid methyl ester, which is then hydrolyzed under the action of base to obtain 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, and finally reacts with cyclopropyl(piperazin-1-yl)methyl ketone hydrochloride under the action of condensation agent and base to obtain crude olaparib. The relevant crude product is recrystallized from N,N-dimethylformamide to obtain the finished olaparib product. The reaction route is as follows:

[0008]

[0009] However, the above processes all require the use of boronic acid derivatives for the reaction, which are expensive. In addition, the preparation of related boronic acid intermediates requires the use of halides and then Grignard reactions. The reaction and operating conditions are relatively harsh and dangerous.

[0010] To solve the above problems, patent CN108129397B uses phthaloyl hydrazide as the starting material, reacts with phosphorus oxychloride to generate 1-chloro-4-carbonylphthalazine, and then reacts with 2-fluoro-5-bromomethyl ethyl benzoate to generate 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazine-1-yl)methyl]ethyl benzoate through Nigishi coupling reaction; then 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazine-1-yl)methyl]benzoic acid is obtained through alkaline hydrolysis; the carboxyl group is first activated by pivaloyl chloride, and then reacts with 1-(cyclopropylcarbonyl)-piperazine to generate Olaparib. However, this process requires the preparation of an organic zinc reagent to activate the aromatic chloride group, which is cumbersome to operate and is easily restricted in large-scale production. In addition, the Nigishi coupling reaction known in the art is difficult to scale up due to safety issues and cannot be used industrially. The reaction route is as follows:

[0011]

[0012] As can be seen from the above, 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid methyl (ethyl) ester (I) is a key intermediate in the preparation of Olaparib, and its preparation will directly affect the production, market supply and quality of the drug. The specific structural formula is shown below:

[0013]

[0014] In view of the fact that the preparation method of 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid methyl (ethyl) ester (I) in the existing process has many shortcomings in terms of process safety, cumbersome operation, etc. Therefore, it is still a problem to be solved to study and find a reaction route suitable for the industrial production of 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid methyl (ethyl) ester (I) with mild reaction conditions, simple operation process, high product yield and high purity. Summary of the invention

[0015] In view of the problems existing in the prior art, the present invention provides a novel method for preparing 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid methyl (ethyl) ester (I), a key intermediate of Olaparib. The target product prepared by the method has high purity and yield, mild reaction conditions, safer operation, and is suitable for industrial scale-up production.

[0016] The specific technical solutions of the present invention are as follows:

[0017] A method for preparing an olaparib intermediate, using SM-1 and SM-2 as raw materials, reacting in the presence of a catalyst, a ligand, manganese powder and an additive to obtain compound I, the reaction formula is as follows:

[0018]

[0019] Wherein X1, X2 are selected from one of Cl and Br respectively, and R is selected from one of Me and Et.

[0020] Preferably, a method for preparing an olaparib intermediate comprises the following steps:

[0021] SM-1, SM-2, catalyst, ligand, manganese powder, additives and trace solvent are added to a ball mill, inert gas protection is introduced, stainless steel balls are added for ball milling reaction, and after the reaction is completed, the target compound I is obtained through post-treatment.

[0022] Preferably, the catalyst is one of NiCl2 or its dimethyl ether complex (NiCl2·DME).

[0023] Preferably, the ligand is one of 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, preferably 1,10-phenanthroline and 3,4,7,8-tetramethyl-1,10-phenanthroline.

[0024] Preferably, the additive is one of KI and KF, preferably KI.

[0025] Preferably, the feed molar ratio of the catalyst to the ligand is 1:1.

[0026] Preferably, the molar ratio of the compound SM-1 to the compound SM-2 is 1:1.2 to 2.0, preferably 1:1.5.

[0027] Preferably, the molar ratio of the compound SM-1 to the catalyst, manganese powder and additive is 1:0.01-0.05:1.5-3.5:0.05-0.3, preferably 1:0.03:2.0:0.1.

[0028] Preferably, the solvent is one of DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), and NMP (N-methylpyrrolidone), preferably DMA.

[0029] Preferably, the mass volume ratio of the compound SM-1 to the solvent is 1:0.5-3 g / ml, preferably 1:1.5 g / ml.

[0030] Preferably, the inert gas is one of argon and nitrogen.

[0031] The size and quantity of the stainless steel balls can be reasonably selected according to the reaction scale.

[0032] In a laboratory-scale embodiment, the size of the stainless steel balls may be 5-10 mm, and the number of the stainless steel balls may be 8-20.

[0033] Preferably, the ball milling speed is 350 to 600 rpm, preferably 450 to 550 rpm.

[0034] Preferably, the post-treatment step is: transferring the reaction mixture to a flask, adding an organic solvent to dissolve, filtering, concentrating the filtrate, beating, filtering, and drying the filter cake to obtain compound I. In a preferred embodiment, the organic solvent is one of dichloromethane, chloroform, and ethyl acetate.

[0035] The slurrying solvent includes slurrying solvents of Compound I known in the art, including but not limited to isopropanol and methanol / ethyl acetate (2:1 v / v).

[0036] The drying is a conventional drying method in the art.

[0037] Beneficial effects of the present invention:

[0038] 1. The present invention provides a method for preparing 2-fluoro-5-[(4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid methyl(ethyl) ester (I), a key intermediate of Olaparib. The method uses SM-1 and SM-2 as starting materials, and directly prepares the target compound I by dehalogenation coupling under nickel catalysis. The synthesis steps are short, and the operation is simple and safe.

[0039] 2. The present invention effectively solves the problem in the prior art coupling that when the starting halide is activated with boric acid or organozinc, a dangerous unit operation is required, resulting in cumbersome operation and easy limitation in large-scale production.

[0040] 3. The preparation process of the olaparib intermediate provided by the present invention is simple to operate and easy to scale up. The obtained product has a high yield and purity and is suitable for industrial production. DETAILED DESCRIPTION

[0041] 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.

[0042] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0043] Example 1

[0044] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Br, 37.06 g, 0.15 mol), NiCl2·DME (3%, 0.66 g), 1,10-phenanthroline (3%, 0.54 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMA (33.75 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 450 rpm. After about 2 hours, the reaction was completed, and the reaction mixture was transferred to a flask, dichloromethane (500 ml) was added to dissolve it, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 95.5% and a purity of 99.90%.

[0045] Example 2

[0046] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Br, 49.41 g, 0.20 mol), NiCl2·DME (3%, 0.66 g), 1,10-phenanthroline (3%, 0.54 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMA (33.75 ml) were added to a ball mill, and nitrogen was introduced for protection. Ten stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 400 rpm. The reaction was completed after about 3 hours. The reaction mixture was transferred to a flask, dissolved in dichloromethane (500 ml), filtered, and the filtrate was concentrated. The filtrate was slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 95.0% and a purity of 99.83%.

[0047] Example 3

[0048] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Br, 29.65 g, 0.12 mol), NiCl2·DME (3%, 0.66 g), 1,10-phenanthroline (3%, 0.54 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMA (33.75 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 6 mm) were added and ball milled at a speed of 550 rpm. After about 2 hours, the reaction was completed, and the reaction mixture was transferred to a flask, dichloromethane (500 ml) was added to dissolve it, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 94.3% and a purity of 99.81%.

[0049] Example 4

[0050] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Br, 37.06 g, 0.15 mol), NiCl2·DME (5%, 1.10 g), 1,10-phenanthroline (5%, 0.90 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMF (33.75 ml) were added into a ball mill, nitrogen was introduced for protection, 8 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 450 rpm. After about 3 hours, the reaction was completed, and the reaction mixture was transferred to a flask, dichloromethane (500 ml) was added to dissolve it, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 94.8% and a purity of 99.85%.

[0051] Example 5

[0052] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Cl, 30.40 g, 0.15 mol), NiCl2·DME (1%, 0.22 g), 1,10-phenanthroline (1%, 0.18 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMA (33.75 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 350 rpm. After about 4 hours, the reaction was completed, and the reaction mixture was transferred to a flask, dichloromethane (500 ml) was added to dissolve it, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 93.5% and a purity of 99.80%.

[0053] Example 6

[0054] SM-1 (X1 = Br, 22.50 g, 0.1 mol), SM-2 (X2 = Cl, 30.40 g, 0.15 mol), NiCl2·DME (1%, 0.22 g), 2,2'-bipyridine (1%, 0.16 g), manganese powder (11.0 g, 0.2 mol), KI (1.66 g, 0.01 mol) and DMA (33.75 ml) were added into a ball mill, nitrogen was introduced, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 350 rpm. The reaction was completed after about 4 hours. The reaction mixture was transferred to a flask, dichloromethane (500 ml) was added to dissolve it, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Me) with a yield of 92.6% and a purity of 99.74%.

[0055] Example 7

[0056] SM-1 (X1 = Cl, 18.06 g, 0.1 mol), SM-2 (X2 = Br, 39.16 g, 0.15 mol), NiCl2·DME (3%, 0.66 g), 1,10-phenanthroline (3%, 0.54 g), manganese powder (11.0 g, 0.2 mol), KI (4.98 g, 0.03 mol) and DMA (54.18 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 450 rpm. After about 2 hours, the reaction was completed, and the reaction mixture was transferred to a flask, ethyl acetate (500 ml) was added to dissolve, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Et) with a yield of 94.4% and a purity of 99.88%.

[0057] Example 8

[0058] SM-1 (X1 = Cl, 18.06 g, 0.1 mol), SM-2 (X2 = Br, 39.16 g, 0.15 mol), NiCl2·DME (3%, 0.66 g), 1,10-phenanthroline (3%, 0.54 g), manganese powder (11.0 g, 0.2 mol), KI (0.83 g, 0.005 mol) and DMA (54.18 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 450 rpm. After about 2 hours, the reaction was completed, and the reaction mixture was transferred to a flask, ethyl acetate (500 ml) was added to dissolve, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Et) with a yield of 93.2% and a purity of 99.83%.

[0059] Example 9

[0060] SM-1 (X1 = Cl, 18.06 g, 0.1 mol), SM-2 (X2 = Cl, 32.50 g, 0.15 mol), NiCl2·DME (3%, 0.66 g), 3,4,7,8-tetramethyl-1,10-phenanthroline (3%, 1.10 g), manganese powder (11.0 g, 0.2 mol), KF (0.29 g, 0.005 mol) and NMP (9.03 ml) were added into a ball mill, nitrogen was introduced for protection, 16 stainless steel balls (φ = 8 mm) were added and ball milled at a speed of 450 rpm. After about 4 hours, the reaction was completed, and the reaction mixture was transferred to a flask, ethyl acetate (500 ml) was added to dissolve, and then filtered. The filtrate was concentrated, slurried with isopropanol, filtered, and the filter cake was dried to obtain compound I (R = Et) with a yield of 92.8% and a purity of 99.73%.

Claims

1. A method for preparing an olaparib intermediate, characterized in that: Using SM-1 and SM-2 as raw materials, in the presence of a catalyst, a ligand, manganese powder and an additive, a reaction is performed to obtain compound I. The reaction formula is as follows: Wherein X1, X2 are selected from one of Cl and Br respectively, and R is selected from one of Me and Et.

2. The preparation method according to claim 1, characterized in that: The specific steps include: SM-1, SM-2, catalyst, ligand, manganese powder, additives and trace solvent are added to a ball mill, inert gas protection is introduced, stainless steel balls are added for ball milling reaction, and after the reaction is completed, the target compound I is obtained through post-treatment.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The catalyst is one of NiCl2 or NiCl2·DME; the ligand is one of 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, preferably 1,10-phenanthroline and 3,4,7,8-tetramethyl-1,10-phenanthroline.

4. The preparation method according to any one of claims 1 to 2, characterized in that: The additive is one of KI and KF, preferably KI.

5. The preparation method according to any one of claims 1 to 2, characterized in that: The molar ratio of the compound SM-1 to the compound SM-2 is 1:1.2 to 2.0, preferably 1:1.

5.

6. The preparation method according to any one of claims 1-2, characterized in that: The feed molar ratio of the catalyst to the ligand is 1:

1.

7. The preparation method according to any one of claims 1 to 2, characterized in that: The molar ratio of the compound SM-1 to the catalyst, manganese powder and additive is 1:0.01-0.05:1.5-3.5:0.05-0.3, preferably 1:0.03:2.0:0.

1.

8. The preparation method according to any one of claims 1-2, characterized in that: The solvent is one of DMF, DMA and NMP; the mass volume ratio of the compound SM-1 to the solvent is 1:0.5-3 g / ml.

9. The preparation method according to any one of claims 1 to 2, characterized in that: The ball milling speed is 350-600 rpm, preferably 450-550 rpm.

10. The preparation method according to claim 2, characterized in that: The post-treatment steps are: transferring the reaction mixture to a flask, adding an organic solvent to dissolve, filtering, concentrating the filtrate, slurrying, filtering, and drying the filter cake to obtain compound I.

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