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Preparation method and intermediate of compound for inhibiting activity of PARP

A compound and active technology, applied in the field of compound preparation, can solve the problems of no industrial production, low purity and yield of compound B, difficult purification and quality control, etc.

Active Publication Date: 2018-11-16
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Wherein step 2 adopts trifluoroacetic acid to deprotect, and the above-mentioned intermediate (II) of generation is trifluoroacetic acid salt, and character is oily substance, and is difficult to purify and quality control, causes the purity and the yield of compound B obtained in the above-mentioned reaction formula low and does not take advantage of industrial production

Method used

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  • Preparation method and intermediate of compound for inhibiting activity of PARP
  • Preparation method and intermediate of compound for inhibiting activity of PARP
  • Preparation method and intermediate of compound for inhibiting activity of PARP

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1: (1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5- Preparation of tert-butyl diazabicyclo[2,2,1]heptane-2-carboxylate

[0107] Add dichloromethane (700ml), 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (70g, 0.24mol) to the reaction flask successively, (1S,4S)-2,5-Diazabicyclo[2,2,1]heptane-2-carboxylic acid tert-butyl ester (71.4g, 0.36mol) and 2-(7-azobenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (136.5g, 0.36mol), stirring. N,N-diisopropylethylamine (70.0 g, 0.54 mol) was added dropwise, stirred at room temperature for 2 hours, and the reaction of raw materials was monitored by TLC to complete. Add 700ml of water, stir, separate the liquids, wash the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a brown oil with a mass of 157.2g.

Embodiment 2

[0108] Example 2: (1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5- Preparation of tert-butyl diazabicyclo[2,2,1]heptane-2-carboxylate

[0109] Add 500ml of dichloromethane, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (70g, 0.24mol), (1S ,4S)-tert-butyl 2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (71.4 g, 0.36 mol), stirred. 1-Hydroxybenzotriazole (HOBT) (48.6 g, 0.36 mol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (69.0 g , 0.36mol). The temperature was controlled at 10°C, and triethylamine (36.4g, 0.36mol) was added dropwise. After the dropping was completed, the reaction was stirred at a temperature of 10°C for about 4 hours, and the reaction of the raw materials was monitored by TLC. Add 500ml of water, stir, separate, wash the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate at 40°C under reduced pressure to obtain a white solid with a mass of 148g.

Embodiment 3

[0110] Example 3: (1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)2,5-di Preparation of tert-butyl azabicyclo[2,2,1]heptane-2-carboxylate

[0111] Add 500ml of dichloromethane, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (70g, 0.24mol), (1S ,4S)-tert-butyl 2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (47.6 g, 0.24 mol), stirred. HOBT (39.2 g, 0.29 mol) was added followed by EDCI (55.6 g, 0.29 mol). The temperature was controlled at 10°C, and N,N-diisopropylethylamine (37.6 g, 0.29 mol) was added dropwise. After dropping, the temperature was controlled at 40° C. and the reaction was stirred for about 24 hours. TLC monitored the complete reaction of the raw materials. Add 500ml of water, stir, separate liquids, wash the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate at 40°C under reduced pressure.

[0112] A white solid with a mass of 152 g was obtained.

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Abstract

The invention discloses a preparation method and an intermediate of a compound for inhibiting the activity of PARP. The method greatly improves the purity and the yield of the compound, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of a compound that inhibits PARP activity and an intermediate thereof. Background technique [0002] PARP is an abbreviation for "poly(ADP-ribose) polymerase". Tumor cells use the PARP enzyme to repair DNA damage, including that caused by chemotherapy. The researchers are investigating whether drugs that inhibit the PARP enzyme also weaken this self-repair mechanism and make tumor cells more sensitive to treatment, accelerating tumor cell death. [0003] PARP inhibitors are a family of pharmacological inhibitors of poly ADP ribose polymerase, which are important for promoting DNA repair, controlling RNA transcription, regulating cell death and immune response. Therefore, there are various indications for the development of PARP inhibitors, the most important indication being for the treatment of tumors. Several forms of BRCA-deficient tumor cells are more dependen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/08A61P9/00A61P9/02A61P9/10A61P25/16A61P27/02A61P37/06A61P19/02A61P1/00A61P1/04A61P25/00A61P3/10A61P1/18A61P35/00A61K31/502
CPCA61P1/00A61P1/04A61P1/18A61P3/10A61P9/00A61P9/02A61P9/10A61P19/02A61P25/00A61P25/16A61P27/02A61P29/00A61P31/00A61P31/12A61P35/00A61P37/06C07D487/08Y02P20/55
Inventor 蔡鸿飞焦育红金远锋祝盼虎蔡群芳李必文钟万德翁玉芳
Owner SHANGHAI DE NOVO PHARMA
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