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Preparation method of Abemaciclib intermediate

A compound and selected technology, applied in the field of medicine and chemical industry, can solve the problems of low yield, harsh reaction conditions, difficult reaction and the like

Active Publication Date: 2017-01-11
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] According to the method disclosed in the above-mentioned literature, in the actual preparation process, a large amount of raw materials remain in the first step reaction, the reaction is not easy to carry out, and 6-bromo-pyridine-3-carbaldehyde is easily reduced to alcohol by sodium triacetoxyborohydride, and the product yield The yield is low; the first method of the second step reaction needs to use liquid ammonia with strong pungent smell, strong corrosiveness and easy volatilization, the reaction conditions are harsh, and the yield is low. The reagents used in the second method are complex, and The follow-up treatment of the reaction solution is very cumbersome and the yield is low, so it is not suitable for industrial production

Method used

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  • Preparation method of Abemaciclib intermediate
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  • Preparation method of Abemaciclib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 Preparation of 5-(4-ethylpiperazine-1-carbonyl)-2-nitropyridine (compound of formula III)

[0076] Add 6-nitronicotinic acid (10g, 59.5mmol), N-ethylpiperazine (8.15g, 71.4mmol), N,N-diisopropylethylamine (15.37g, 119.0mmol) and 500ml reactor DMF (100ml). The temperature of the reaction system was lowered to 0°C while stirring. PyBOP (34.05 g, 65.5 mmol) was slowly added to the reaction solution, and the reaction solution slowly dissolved. After PyBOP was added, the reaction was continued for 30 minutes, and the temperature of the reaction solution was raised to 25°C. Stop the reaction after reacting for 2 hours, slowly add 500ml of water to the reaction system, separate out the solid, add ethyl acetate and extract three times (each 200ml), the organic phase of the separated gained is washed with saturated saline, dried over anhydrous sodium sulfate, filtered, Concentrate in vacuo and purify by column chromatography (200-300 mesh silica gel, dichloromethane...

Embodiment 2

[0080] Example 2 Preparation of 5-(4-ethylpiperazine-1-carbonyl)pyridin-2-amine (compound of formula IV)

[0081] Add the compound of formula III (10 g, 37.84 mmol), 10% Pd / C (2.5 g, containing 50% water, 1.2 mmol), methanol (250 ml) into a 100 ml reactor. Under stirring, the temperature of the reaction system was raised to 50°C for hydrogenation under normal pressure. After 2 hours of reaction, stop the reaction, filter, wash the filter cake with methanol (10ml), and concentrate the filtrate to obtain 7.5g of the compound of formula IV, yield: 84.3%.

[0082] ESI-MS[M+H] + :235.1537.

[0083] 1 H NMR (300MHz, DMSO-d6): δ7.99 (d, J = 1.5Hz, 1H), 7.42 (dd, J = 8.5, 1.5Hz, 1H), 6.43 (d, J = 8.5Hz, 1H), 6.36 (s, 2H), 3.49 (m, 4H), 2.30-2.50 (m, 6H), 0.99 (t, J=7.2Hz, 3H).

[0084] 13 C NMR (75 MHz, DMSO-d6): δ 167.87, 160.44, 147.83, 136.71, 118.82, 106.71, 52.29, 51.40, 44.77, 11.78.

Embodiment 3

[0085] Example 3 Preparation of 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (compound of formula I)

[0086] Tetrahydrofuran (50ml) was added into a 100ml reactor, and the temperature of the reaction system was lowered to 0°C under the protection of nitrogen. Lithium aluminum hydride (3.1g, 85.2mmol) was first added to tetrahydrofuran, and then the compound of formula IV (5.0g, 21.3mmol ), stop the reaction after reacting at 0°C for 3 hours, slowly add 1N sodium hydroxide dropwise at 0°C, stir, and no gas is released. Dichloromethane was extracted three times (50ml each time). The separated organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by column chromatography (200-300 mesh silica gel, dichloromethane:methanol=200:1, 150:1, 100 : 1 gradient elution, collect single product spot eluent, concentrate), obtain solid 4.1g, yield: 87.2%, HPLC purity 97.2% (area normalization ...

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Abstract

The invention belongs to the field of medicine and chemical industry, and concretely relates to a preparation method of an Abemaciclib intermediate. Nitro and carbonyl of 5-(4-ethyl piperazine-1-carbonyl)-2-nitropyridine are reduced successively, and the Abemaciclib intermediate 5-(4-ethyl-piperazin-1-yl)methyl)pyridin-2-amine is obtained; the raw materials and reagents are easy to obtain, reaction conditions are mild, usage of reagents with toxicity or irritation or strong corrosivity is avoided, the method is green and environmentally friendly, and the preparation is simple and easy to operate; the product has high yield and high purity, and is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an Abemaciclib intermediate. Background technique [0002] Abemaciclib, chemical name [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2 -Methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine, is a CDK4 / 6 inhibitor developed by Eli Lilly and Company for oral treatment of breast cancer. [0003] [0004] CN102264725A discloses the preparation method of Abemaciclib and its intermediate 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Formula I). ​​The preparation method of the intermediate is as follows: [0005] [0006] Reaction of 6-bromo-pyridine-3-carbaldehyde with N-ethylpiperazine in dichloromethane in the presence of sodium triacetoxyborohydride affords 1-(6-bromo-pyridin-3-ylmethyl)- 4-ethyl-piperazine, and then further prepare the compound of formula I under the conditions of cuprous...

Claims

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Application Information

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IPC IPC(8): C07D213/73C07D213/82
CPCC07D213/73C07D213/82
Inventor 朱益忠张喜全刘飞顾红梅汤剑秋朱波汤松王路路
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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