Synthetic method of olaparib

A synthetic method and oxo-generation technology, applied in the direction of organic chemistry, can solve the problems of unfavorable industrial production, difficulty in purification, and high cost of raw materials, and achieve the effects of easy large-scale production, easy control of operating conditions, and mild and easy control of reaction conditions

Pending Publication Date: 2020-02-14
SOUTHEAST UNIV
View PDF3 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Analyzing the above synthesis route, the last step reaction requires the condensation of expensive O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) reaction, the productive rate is 38%, the raw material cost is high and difficult to purify, which is unfavorable for suitability for industrialized production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of olaparib
  • Synthetic method of olaparib
  • Synthetic method of olaparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Preparation of compound 3

[0053] The synthetic route is:

[0054]

[0055] Add sodium formate (1g, 0.018mol) and methanol (16ml) into a round bottom flask, stir, and after cooling down to 0°C, add dimethyl phosphite (2.1ml, 0.022mol) dropwise. O-carboxybenzaldehyde (2.2 g, 0.014 mol) was added slowly, warmed up to room temperature, reacted for 4 h, then methanesulfonic acid (1.3 ml, 0.019 mol) was added dropwise within 10 min, stirred, and concentrated to dryness under reduced pressure. Add water (20ml), extract with dichloromethane, collect the dichloromethane layer, wash with anhydrous Na 2 SO 4 dry. After filtration, it was concentrated under reduced pressure to obtain a white solid (2.6 g, yield 91%).

[0056] The target product compound 3 1 The HNMR data are as follows:

[0057] 1 H-NMR (500MHz, DMSO-d 6 )δ: 3.62(d, J=8Hz, 3H), 3.86(d, J=12Hz, 3H), 6.36(d, J=8Hz, 1H), 7.71(m, 1H), 7.88(m, 2H), 7.98 (m, 1H).

Embodiment 2

[0059] Preparation of compound 4

[0060] The synthetic route is:

[0061]

[0062] Compound 3 (2.6g, 0.011mol) and 2-fluoro-5-formylbenzoic acid (2.1g, 0.012mol) were dissolved in anhydrous tetrahydrofuran (25ml), cooled to 0°C, and triethylamine was slowly added dropwise (1.0ml, 0.007mol), rise to room temperature and react for 5h after dropping, then slowly raise the temperature to 70°C, add hydrazine hydrate (5.1ml, 0.107mol) for 3h, cool down to room temperature, add appropriate amount of hydrochloric acid (2mol / L) adjust the pH to acidity, and no more solids are precipitated. Suction filtration, the product was washed with water and ethyl acetate, and dried to give a yellow solid (1.9g, yield 83%)

[0063] The target product compound 4 1 The HNMR data are as follows:

[0064] 1 H NMR (500MHz, DMSO-d 6 )δ13.13(s,1H),12.60(s,1H),8.29(d,J=7.7Hz,1H),8.00(d,J=8.1Hz,1H),7.92(t,J=7.6Hz, 1H), 7.88–7.81 (m, 2H), 7.60 (ddd, J=7.8, 4.5, 2.4Hz, 1H), 7.26 (dd, J=10.8, 8.4H...

Embodiment 3

[0066] Preparation of Compound 5:

[0067] The synthetic route is:

[0068]

[0069] In a dry environment, compound 4 (1.9g, 0.0063mol) was dissolved in anhydrous dichloromethane under the protection of nitrogen, cooled to 0°C, and oxalyl chloride (2.4ml, 0.025mol) was slowly added dropwise, and rose to At room temperature, add two drops of DMF dropwise, react at room temperature for 2 hours, remove the solvent and excess oxalyl chloride under reduced pressure to obtain 2.1 g of light yellow solid, which is directly put into the next step reaction.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a synthesis method of olaparib, which comprises the following steps: carrying out reaction on dimethyl phosphite and o-carboxybenzaldehyde to generate (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; enabling (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate to react with 2-fluoro-5-formylbenzoic acid to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid with oxalyl chloride to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride to react with piperazine cyclopropyl ketone, so as to generate olaparib. The invention provides a new olaparib synthesis route, the raw materials are easy to obtain, the operation post-treatment is simple, the reaction conditions of each step are mild, and the total yield reaches 93%.

Description

technical field [0001] The present invention relates to drug synthesis, in particular to a synthesis method of olaparib. Background technique [0002] Malignant tumors have received extensive attention worldwide. Breast cancer, ovarian cancer, and cervical cancer are the three major cancers that threaten women's lives, and breast cancer has the highest incidence rate. One out of every 20 women in the world will suffer from breast cancer, while ovarian cancer has the highest death rate. At present, the main means of treating breast cancer and ovarian cancer are still radiotherapy and chemotherapy. But its disadvantage is the production of drug-resistant cells and the low disease-free period and overall survival rate of patients. Especially triple-negative breast cancer has always been a difficult problem in clinical treatment. The occurrence of breast and ovarian cancer is associated with mutations in the BRCA1 / 2 gene. In recent years, polyadenosine diphosphate-ribose po...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 蔡进任敬慧胡心怡魏丽郦于萍黄铭祺
Owner SOUTHEAST UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap