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(R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation

A kind of technology of dimethylaminocarbonyl and aminophosphate, applied in (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy- 4-Nitrophenyl)-1-ethyl-N,N'-bis(ethylidene)amino phosphate, composition and field of use and preparation thereof

Active Publication Date: 2018-07-17
SHENZHEN ASCENTAWITS PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

PR l04 is ineffective in clinical trials

Method used

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  • (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
  • (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation
  • (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis (ethylene)phosphoramidate, compositions and methods for their use and preparation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0088] Example 1. Preparation of compound TH 2870

[0089]

[0090] Compounds 2 to 6 were synthesized as described below.

[0091] a. Synthesis of compound 3:

[0092] in SOCl with DMF (3 drops) 2 (10 mL) to reflux compound 1 (3 g, 16.2 mmol) for 3 h and then remove SOCl under vacuum 2 . The residue was diluted with toluene (5 mL) and used in the next step without further purification.

[0093] Stir MgCl at RT 2 (930mg, 9.8mmol), TEA (4.7mL, 33.4mmol) and dimethyl malonate (1.9mL, 16.6mmol) for 1.5h, followed by the addition of the toluene solution of compound 2 mentioned above. The resulting mixture was stirred at RT for another 1.5 h, then concentrated HCl (4 mL) was added and stirred for 5 min. The mixture was extracted with EtOAc (30mL×3), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. To the residue was added 6N HCl (30 mL) and the mixture was refluxed overnight. The mixture was extracted with EtOAc (30mL×3), dried (Na 2 SO 4 ), filte...

example 2

[0119] Example 2. Alternative preparation of compound TH 2870.

[0120]

[0121] a. Preparation of compound 3

[0122] in SOCl with DMF (10ml) 2 Compound 1 (200 g, 1.08 mol) was refluxed in (700 mL) for 3 hours and then SOCl was removed under vacuum 2 . The residue was diluted with toluene (400 mL) and used in the next step without further purification.

[0123] Stir MgCl at RT 2 (103 g, 1.08 mol), TEA (500 mL, 3.60 mol) and dimethyl malonate (145 g, 1.1 mol) for 1.5 h, then the toluene solution of compound 2 mentioned above was added dropwise. The resulting mixture was stirred for an additional 1.5 h at RT. with H 2 O (2 L) was washed, extracted with EtOAc (2 L x 5), after evaporation, 4N HCl was added until pH 6.0 and stirred for 5 min. The mixture was extracted with EtOAc (2L x 5) and evaporated.

[0124] To the residue was added 6N HCl (1500 mL) and the mixture was refluxed overnight.

[0125] The mixture was extracted with EtOAc (2 L x 5), concentrated, purifi...

example 3

[0135] Example 3. Separation of enantiomers of TH2870 by preparative chiral chromatography

[0136] 983mg of the compound of formula (I) was dissolved in 36mL of methanol, and 1mL was injected into the SFC-80Method Station (Thar, Waters) in CHIRALPAK OZ-H 4.6 × 250mm, 5μm (Daicel), and in CO 2 Elute at this flow rate in a mixture of methanol / methanol (65-60 / 35-40). The enantiomer of formula (Ia) (configuration (R)) was obtained in 86.5% yield and 100% enantiomeric purity. The enantiomer of formula (Ib) (configuration (S)) was obtained in 83.8% yield and 100% enantiomeric purity. Figure 1 shows the purity check of TH 2870 Enantiomer 1 (TH3423) and TH 2870 Enantiomer 2 (TH3424 or AST 106) after chiral separation by LCMS.

[0137] Chiral Synthesis of TH 3423 and 3424

[0138]

[0139] Compound 2

[0140] in SOCl with DMF (2.5 mL) 2 (150 mL) was refluxed for 5 h to obtain a clear solution of compound 1 (65 g) and then the SOCl was removed under vacuum 2 . The residue wa...

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PUM

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Abstract

Provided herein are optically active compounds of the formulae (ii); and (III) and pharmaceutical compositions thereof. Also provided herein are processes of making these compounds and resolving the racemic mixture or the enrichment of same with in one of its enantiomers to provide (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-nitrophenyl)-1-ethyl-N,N'-bis(ethylene)phosphoramidate, andmethods of treating cancer comprising administering such compounds.

Description

technical field [0001] The present invention provides an optically active form of the compound 1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy-4-nitrophenyl)-1-ethyl-N, N'-bis(ethylenyl)phosphoramidate, the pharmaceutical composition of these compounds and the method for treating cancer, and the compound (R,S)-1-(3-(3-N,N-two These optically active forms or enriched One of its enantiomers, or stereoselectively synthesized optically pure (R) and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy-4-nitro Phenyl)-1-ethyl-N,N'-bis(ethylidene) phosphoramidate method. Background technique [0002] Cancer is one of the main causes of human morbidity and death. Cancer treatment is challenging because it is difficult to kill cancer cells without damaging or killing normal cells. Damage or killing of normal cells during cancer treatment can cause adverse side effects in the patient and can limit the amount of anticancer drugs administered to the cancer patient. [0003] Aldo-keto reductase ...

Claims

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Application Information

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IPC IPC(8): C07F9/564C07F9/22C07B55/00
CPCC07F9/564C07F9/2429A61K31/664A61P35/00A61P35/02A61P43/00
Inventor 段建新曹冶宇蔡晓宏矫海龙马靖原马克·马特西
Owner SHENZHEN ASCENTAWITS PHARM TECH CO LTD
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