Preparation method for ceritinib analog

A technology of ceritinib and analogs, which is applied in the field of compound preparation and achieves the effects of easily controllable conditions, high yield and low cost

Active Publication Date: 2019-08-20
EAST CHINA NORMAL UNIV +1
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Problems solved by technology

[0004] Therefore, in the synthesis and quality inspection of ceritinib, the artificially synthesized ceritinib analog, that is, compound V, can be used as a standard preparation, compared with the impurities in ceritinib products, and the ceritinib drug The quality detection of has very important significance, but at present about compound V5-chloro-N 2 -(2-isobutyl-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N 4 There are few reports on the synthesis of -(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride

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  • Preparation method for ceritinib analog
  • Preparation method for ceritinib analog
  • Preparation method for ceritinib analog

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Embodiment 1

[0020] 1.1 Compound I is 2,2,2-trichloroethyl 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)- Synthesis of tert-Butyl Carboxylate

[0021] Dissolve 1 g of 1-benzyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine in 7 mL of acetonitrile in a one-necked bottle , Add 0.58g trichloroethyl chloroformate, react at room temperature. The reaction was carried out for 2 hours, and TLC detected that the reaction of the raw materials was complete. The acetonitrile was evaporated to dryness, and the volume ratio of ethyl acetate to petroleum ether was 1:8 for column chromatography purification. Obtain compound I namely 2,2,2-trichloroethyl 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)- 1.07 g of tert-butyl carboxylate, the yield was 87%.

[0022] 1 H NMR: (500MHz, CDCl 3 )δ7.64(s,1H),6.80(s,1H),5.67(d,J=17.9Hz,1H),4.83(s,2H),4.65-4.61(m,1H),4.23(d,J =23.2Hz,2H),3.80(d,J=25.1Hz,2H),2.40(br,2H),2.26(s,3H),1.40(d,J=6.1Hz,6H).

...

Embodiment 2

[0033] 2.1 Compound II is 2,2,2-trichloroethyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxyl Synthesis of tert-butyl ester

[0034] 4.0g 2,2,2-trichloroethyl 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H )-tert-butyl carboxylate was dissolved in 40 mL of absolute ethanol, 0.29 g of ferric chloride was added, 0.58 g of activated carbon was added, and 10.64 g of 50% hydrazine hydrate was added, and the temperature was raised to 75°C. After 6 hours of reaction, TLC detected that the reaction of raw materials was complete. Suction filter with a pad of Celite, evaporate to dryness of absolute ethanol, add dichloromethane, wash with water twice, separate the organic phase, dry over anhydrous sodium sulfate, evaporate to dryness, and use ethyl acetate and petroleum ether at a volume ratio of 1:5 Purification by column chromatography was performed. Obtain compound II namely 2,2,2-trichloroethyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-...

Embodiment 3

[0046] 3.1 Synthesis of Compound III, namely 2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)aniline dihydrochloride

[0047] 1.92g of 2,2,2-trichloroethyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-3,6-dihydropyridine-1(2H )-tert-butyl carboxylate was dissolved in 15 mL of mixed solvent (V (acetonitrile): V (glacial acetic acid) = 4: 1), added 9.6 g of zinc powder, and reacted at room temperature. The reaction was carried out for 4 hours, and TLC detected that the reaction of the raw materials was complete. Suction filter with a pad of celite, evaporate the reaction solvent to dryness, add saturated sodium carbonate solution to the system to adjust the pH to 9-10, extract with dichloromethane, wash with water, dry over anhydrous sodium sulfate, and evaporate to dryness. The obtained compound was dissolved in 5 mL of anhydrous methanol, 0.57 mL of concentrated hydrochloric acid was added, stirred at room temperature for 20 min, and evaporated to dryness of anhydrous meth...

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Abstract

The invention discloses a preparation method for a ceritinib analog, i.e., 5-chloro-N2-(2-isobutyl-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride. The method comprises the following steps: with 1-benzyl-4-(5-isopropyloxy)-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine as a starting material, subjecting the starting material and trichloroethyl chloroformate to a nucleophilic substitution reaction so as to form a compound I; then reducing the nitro group of the compound into an amino group under the action of a reducing agent so as to form a compound II; then carrying out deprotection under the action of a reducing agent to obtain a compound III; and finally, subjecting the hydrochloride of the compound III and acompound IV to a nucleophilic substitution reaction to form a compound V, i.e., 5-chloro-N2-(2-isobutyl-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride. The preparation method of the invention has the advantages of short synthetic route, simple operation, good safety, high product yield, high quality and low synthesis cost.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to ceritinib analogs, namely 5-chloro-N 2 -(2-isobutyl-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N 4 - a preparation method of (2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride. Background technique [0002] Ceritinib is a selective ALK kinase inhibitor indicated for the treatment of non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-positive metastases who have progressed on or cannot tolerate crizotinib treat. At present, in the process of synthesizing ceritinib dihydrochloride (as shown in the left formula), the following impurities will inevitably appear, that is, ceritinib analog compound V (as shown in the right formula): [0003] [0004] Therefore, in the synthesis and quality inspection of ceritinib, the artificially synthesized ceritinib analogue, that is, compound V, can be used as a standard pre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 吴文萱李晓林罗宇占莉康立涛李倩杨世琼
Owner EAST CHINA NORMAL UNIV
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