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Preparation method of pyridylaminopyrimidine derivative and intermediate thereof

A pyrimidine and amine-based technology, which is applied in the field of organic synthesis and the preparation of raw materials, can solve the problems of heavy metal residues, unsuitable for industrial production, and many waste residues

Active Publication Date: 2019-12-24
SHANGHAI ALLIST PHARM CO LTD +1
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  • Abstract
  • Description
  • Claims
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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

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  • Preparation method of pyridylaminopyrimidine derivative and intermediate thereof
  • Preparation method of pyridylaminopyrimidine derivative and intermediate thereof
  • Preparation method of pyridylaminopyrimidine derivative and intermediate thereof

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...

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Abstract

The invention provides a preparation method of a compound 2-[2-(dimethylaminoethyl) methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indole-3-yl) pyrimidine-2-amino]-6-(2, 2, 2-trifluoroethoxy) pyridine asshown in a formula I, a used intermediate and a preparation method of a related intermediate. According to the method, 3-(2-chloropyrimidine-4-yl)-1-methyl-1H-indole and a compound shown as a formulaVII are subjected to a condensation reaction, a substitution reaction, a reduction reaction, an acylation reaction and an elimination reaction, and a compound shown as a formula I is obtained. The preparation method disclosed by the invention is environment-friendly, low in cost, mild in condition, simple to operate, high in yield, high in final product purity and suitable for industrial 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

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Application Information

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