Preparation method and intermediate of pyridineaminopyrimidine derivatives

A pyrimidine and amine-based technology is applied in the fields of organic synthesis and the preparation of raw materials, which can solve the problems of many steps in the overall preparation route, unsuitable for industrial production, troublesome post-processing, etc., achieves low requirements for reaction equipment, promotes complete reduction reaction, The effect of improving the reaction efficiency

Active Publication Date: 2021-06-01
SHANGHAI ALLIST PHARM CO LTD +1
View PDF7 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Iron powder / ammonium chloride is used to reduce 6-chloro-2-trifluoroethoxyl-3-nitropyridine in this preparation method, aftertreatment is troublesome, produces more waste residue, is unfavorable for environmental protection; In the route, coupling reaction and Heavy metals are used in the hydrogenation reduction reaction, which is costly, and heavy metals will remain in the product; the last step of the acylation reaction, the yield is too low, only 23%; the post-processing of the multi-step reaction uses column chromatography; the overall preparation route has many steps , the total yield is only 2.3%, which is not suitable for industrial 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
  • Preparation method and intermediate of pyridineaminopyrimidine derivatives
  • Preparation method and intermediate of pyridineaminopyrimidine derivatives
  • Preparation method and intermediate of pyridineaminopyrimidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1: Preparation of 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (XI-1)

[0139] Add toluene (24.0L) to the reaction kettle, then add 2,6-dichloro-3-nitropyridine (3000g, 15.54mol), adjust the internal temperature between -20°C and -10°C, and add sodium in batches Hydrogen (933 g, 23.33 mol). A solution of 2,2,2-trifluoroethanol (1586 g, 16.00 mol) in toluene (6.0 L) was added dropwise. After 2 hours of reaction, TLC and HPLC monitored the end point of the reaction. After the reaction was complete, 10% ammonium chloride solution (6.0 L) was added dropwise. Let stand, layer. The organic phase was washed with water (6.0 L) and concentrated under reduced pressure. Add ethyl acetate (0.3L), heat up to 40-50°C, add n-heptane (2.7L) dropwise, cool down to -15 to -5°C to continue crystallization for 3 hours, and filter with suction. 3017 g of product solids were obtained with a yield of 75.65%.

[0140] 1 H NMR (500MHz, DMSO-d6) δ8.60 (d, J = 8.0Hz, 1H), 7.5...

Embodiment 2

[0143] Example 2: Preparation of 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (X-1)

[0144] At room temperature, add acetonitrile (21.0L) and water (21.0L) to the reaction kettle, start stirring, and add the 6-chloro-3-nitro-2-(2,2,2-trifluoroethane obtained in Example 1 Oxy)pyridine (3017.0g, 11.76mol), add hydrosulfite (15.1Kg, 70.54mol). React for 2 hours under the condition of controlling the temperature at 27-33°C. 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) was added dropwise, and the reaction was continued for 1.5 hours. Solid sodium bicarbonate (12.8 Kg, 12.96 mol) was added. After filtration, the mother liquor was separated into layers, and the organic phase was washed with saturated brine (21.0 L), and concentrated under reduced pressure to obtain an oily substance.

[0145] 1 H NMR (500MHz, DMSO-d6) δ7.03(d, J=8.0Hz, 1H), 6.90(d, J=8.0Hz, 1H), 5.21(s, 2H), 4.93(q, J=9.0Hz ,2H);

[0146] 13 C NMR (126MHz, DMSO-d6) δ 148.16, 131.72, 130.55, 12...

Embodiment 3

[0148] Example 3: Preparation of 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (IX-1)

[0149] At room temperature, dichloromethane (10.4 L) was added to the reaction kettle, stirring was started, and 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (2664 g , 11.76mol), diisopropylethylamine (2279g, 17.64mol) was added, the temperature was controlled from -15 to -10°C, and a solution of trifluoroacetic anhydride (2963g, 14.11mol) in dichloromethane (5.2L) was added dropwise After dripping, continue to stir for 20 minutes. Water (13.0L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the theoretical calculation was carried out to the next step reaction.

[0150] 1 H NMR (400MHz, DMSO-d6) δ11.23(s, 7H), 7.95(d, J=8.0Hz, 1H), 7.34(d, J=8.0Hz, 1H), 5.03(q, J=8.9Hz ,2H);

[0151]13 C NMR (101MHz, DMSO-d6) δ155.74(q, J=46.6Hz), 155.60, 145.37, 140.24, 124.01(q, J=278.8Hz), 119.07, 118.30, 1...

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 present invention provides a compound of formula I 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indole-3 -yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine, the preparation method of the intermediates used and related intermediates. In the method, the compound of formula I is obtained through condensation reaction, substitution reaction, reduction reaction, acylation reaction and elimination reaction of 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole and the compound of formula VII. The preparation method of the invention is environmentally friendly, low in cost, mild in condition, simple in operation, high in yield, high in purity of the final product, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis and preparation of raw materials, in particular to N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-( 2,2,2-Trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}propene Methods of amides and their intermediates. Background technique [0002] The compound N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5- {[4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide is an epidermal growth factor receptor (EGFR) inhibitor that The inhibitory activity of EGFR T790M drug-resistant mutation is significantly higher than that of wild-type EGFR (WT EGFR). It has good selectivity and low side effects. It can be used to treat cancer, especially non-small cell lung cancer. in the clinical stage. [0003] [0004] CN105315259A patent application protects the compound of formula I, and discloses its preparation method as follows, [...

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 Patents(China)
IPC IPC(8): C07D401/14C07D213/75C07D213/73
CPCC07D213/73C07D213/75C07D401/14
Inventor 张强罗会兵
Owner SHANGHAI ALLIST PHARM CO LTD
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