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Key intermediate of PARP inhibitor and preparation method thereof

An intermediate and inhibitor technology, applied in the field of medicine, can solve the problems of high cost, low separation yield and pollution, and achieve the effects of mild conditions, good yield, and high chemical and optical purity.

Inactive Publication Date: 2018-12-14
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This route uses precious metals such as rhodium, silver, etc., which has high cost, low split yield and serious pollution

Method used

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  • Key intermediate of PARP inhibitor and preparation method thereof
  • Key intermediate of PARP inhibitor and preparation method thereof
  • Key intermediate of PARP inhibitor and preparation method thereof

Examples

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Effect test

Embodiment 1

[0050] (1) Preparation of compound 2(S)-N-tert-butylsulfinyl-2-(4-bromophenyl)-1-methoxyethane-1-imine

[0051] Compound SM1 (23g, 0.1mol, 1eq) and SM2 (12.1g, 0.1mol, 1eq) were dissolved in 50ml tetrahydrofuran, and Ti(OEt) was added 4 (20ml, 0.1mol, 1eq), protected by nitrogen, heated to reflux for 6h, the reaction solution was poured into saturated brine, filtered with suction, the filtrate was dried over anhydrous sodium sulfate, and concentrated to obtain 32.5g of yellow oil with a yield of 97.9%. 1 H-NMR (CDCl 3 ,400MHz): δ1.20(9H,s),3.75(3H,s),3.96(1H,d),4.09(1H,d),6.94-7.05(2H,m),7.25-7.37(2H,m ).

[0052] (2) Compound 3(S)-N-tert-butylsulfinyl-2-(4-bromophenyl)-2R-(3-methylsulfonate propyl)-1-methoxyethane- Preparation of 1-imine

[0053] Take the above oil (10g, 30mmol, 1eq), add 50ml of anhydrous THF, cool to -78°C, slowly add LiHMDS (1M, 60ml, 2eq, 60mmol), stir for 30min, slowly add 3-bromopropyl methanesulfonic acid Ester (7.16g, 33mmol, 1.1eq), reacted at t...

Embodiment 2

[0062] (1) Preparation of compound 2(S)-N-tert-butylsulfinyl-2-(4-bromophenyl)-1-methoxyethane-1-imine

[0063] Compounds SM1 (23g, 0.1mol, 1eq) and SM2 (13.3g, 0.11mol, 1.1eq) were dissolved in 50ml of tetrahydrofuran, and Ti(OEt) was added 4 (60ml, 0.3mol, 3eq), under nitrogen protection, heated to reflux for 6h, the reaction solution was poured into saturated brine, filtered with suction, the filtrate was dried over anhydrous sodium sulfate, concentrated to give 32.6g of yellow oil, yield 98.2%.

[0064] (2) Compound 3(S)-N-tert-butylsulfinyl-2-(4-bromophenyl)-2R-(3-methylsulfonate propyl)-1-methoxyethane- Preparation of 1-imine

[0065] Take the above oil (10g, 30mmol, 1eq), add 50ml of anhydrous THF, cool to -78°C, slowly add LiHMDS (1M, 120ml, 4eq, 120mmol), stir for 30min, slowly add 3-bromopropyl methanesulfonic acid Ester (7.81g, 36mmol, 1.2eq), reacted at this temperature for 2h, then poured the reaction solution into a saturated ammonium chloride solution to quenc...

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Abstract

The invention discloses a preparation method of Niraprib of a PARP inhibitor and two key intermediates used in the preparation method. The preparation method comprises the following steps: taking 4-methyl alpha-bromophenylacetate and (S)-tert-butanesulfinyl amide as raw materials, and performing condensation, asymmetry alkylation, reduction and coupling on the raw materials, so as to obtain a keyintermediate compound 5; condensing and coupling the compound 5, so as to obtain a compound 6; hydrolyzing the compound 6 under the action of p-toluenesulfonic acid to remove a protecting group, so asto obtain a target product Niraprib. The preparation method has the beneficial effects that the conventional resolution and chiral source methods are overcome by introducing the asymmetry alkylationinduced chirality of a chiral auxiliary, so that the preparation method is simple in operation, mild in conditions, good in yield and relatively high in chemical purity and optical purity; in addition, key intermediates 5 and SM3 are condensed to form a target compound 1, so that the original patent is broken through, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a key intermediate of a PARP inhibitor and a preparation method thereof. Background technique [0002] Niraprib (compound 1) is a new oral PARP-1 inhibitor developed by Merck (taken over by Tesaro after 2012). It was approved by the US FDA in March 2017 and is mainly used clinically to treat recurrent Epithelial ovarian, fallopian tube, or primary peritoneal cancer IDE maintenance therapy (aimed at slowing cancer growth). Niraprib is currently the only PARP inhibitor on the market that can significantly prolong the progression-free survival of patients with recurrent ovarian cancer regardless of the patient's BRCA mutation or biomarker status. Its sales peak is expected to reach 2 billion per year Dollar. [0003] Its structural formula is as follows: [0004] [0005] Niraprib (compound 1) [0006] At present, there are two main types of Niraparib synthesis m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10C07D211/96
CPCC07B2200/07C07D211/96C07D401/10Y02P20/55
Inventor 朱怡君孙光祥王兵
Owner CHANGZHOU PHARMA FACTORY
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