Deuterated palbociclib derivative, and preparation method and application thereof

A derivative and deuterium technology, applied in the field of pharmaceutical compounds, can solve the problems of loose cell connections, life-threatening, easy to fall off, etc.

Active Publication Date: 2015-03-25
TYK MEDICINES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The mammary gland is not an important organ to maintain human life activities, breast cancer in situ is not fatal; but because breast cancer cells lose the characteristics of normal cells, the connections between cells are loose and easy to fall off; once the cancer cells fall off, the free cancer cells can Disseminate the whole body with blood or lymph fluid, form metastases, and endanger life

Method used

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  • Deuterated palbociclib derivative, and preparation method and application thereof
  • Deuterated palbociclib derivative, and preparation method and application thereof
  • Deuterated palbociclib derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] The synthetic route of deuterated cyclopentylamine hydrochloride involves chemical formula as:

[0106]

[0107] Deuterated cyclopentylamine hydrochloride is prepared by a method comprising the following steps:

[0108] a) Synthesis of compound 2: take 2.2g of LiAlD 4 Add 100ml of diethyl ether (Et 2(0), the system was cooled to 0°C; under the protection of nitrogen, slowly dropwise added an ether solution containing 8g of cyclopentanone (compound 1), after the dropwise addition, the system was warmed up to room temperature and continued to react for 1h; after the reaction, Add saturated NH 4 Cl solution quenched the reaction, extracted three times with ether, combined the organic phases, dried and concentrated to obtain 8 g of colorless transparent liquid compound 2;

[0109] The NMR information of compound 2 is: 1 H NMR (400MHz, CDCl 3 ): δ1.78-1.74(m,4H),1.58-1.55(m,4H);

[0110] b) Synthesis of Compound 3: Dissolve 5.2g of Compound 2 in 100ml of dichloromet...

Embodiment 2

[0116] The deuterated Palbociclib derivative of the present embodiment has a structural formula as shown in formula (I):

[0117]

[0118] The chemical formula involved in the synthetic route of the deuterated Palbociclib derivative of the present embodiment is as follows:

[0119]

[0120] The preparation method of the deuterated Palbociclib derivative of the present embodiment comprises the following steps:

[0121] 1) Synthesis of Compound 6: Dissolve 7g of compound 5c (deuterated cyclopentylamine hydrochloride, deuterated cyclopentylamine (compound 5)) obtained in Example 1 in 100ml of absolute ethanol, and add 16ml Et 3 N, add 9 g of 2,4-dichloro-5-bromopyrimidine (compound 5a) in batches under stirring conditions (the molar ratio of 2,4-dichloro-5-bromopyrimidine to deuterated cyclopentylamine salt 0.7:1), continue to react for 2 hours after the addition; after the reaction, filter, concentrate the filtrate, add water to precipitate a white solid, add a small amo...

Embodiment 3

[0138] The deuterated Palbociclib derivative of the present embodiment has a structural formula as shown in formula (II):

[0139]

[0140] The chemical formula involved in the synthetic route of the deuterated Palbociclib derivative of the present embodiment is as follows:

[0141]

[0142] The preparation method of the deuterated Palbociclib derivative of the present embodiment comprises the following steps:

[0143] 1) Synthesis of compound 14: Dissolve 7g of cyclopentylamine (compound 5b) in 100ml of absolute ethanol, add 16ml of Et 3 N, under stirring conditions, add 9g of 2,4-dichloro-5-bromopyrimidine (compound 5a) in batches to the system, and continue to react for 2h after the addition; after the reaction, filter, concentrate the filtrate, add water to precipitate a white solid, A small amount of petroleum ether was added to the solid, stirred for 10 minutes and then filtered to obtain 8 g of white solid compound 14;

[0144] The NMR information of compound 14...

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Abstract

The invention discloses a deuterated palbociclib derivative, and a preparation method and an application thereof. A structural formula of the deuterated palbociclib derivative is as shown in a formula (I), a formula (II), a formula (III) or a formula (IV). According to the deuterated palbociclib derivative disclosed by the invention, through selective deuteration of palbociclib, the pharmacokinetic property of the medicine is improved, thus the curative effect, the safety and the tolerance of the medicine are improved. According to the deuterated palbociclib salt disclosed by the invention, the solubility and the dissolution rate of the medicine are improved; a new compound is provided for synthesis of a novel anti-tumor medicine through synthesis of the deuterated palbociclib derivative; and the deuterated palbociclib derivative has similar biologic activity to the palbociclib, and has a good medicine application prospect.

Description

technical field [0001] The invention belongs to the technical field of medical compounds, and specifically relates to a deuterated Palbociclib derivative, and also relates to a preparation method and application of a deuterated Palbociclib derivative. Background technique [0002] Breast cancer is a malignant tumor that occurs in the glandular epithelial tissue of the breast; 99% of breast cancer occurs in women, and only 1% in men. The mammary gland is not an important organ to maintain human life activities, breast cancer in situ is not fatal; but because breast cancer cells lose the characteristics of normal cells, the connections between cells are loose and easy to fall off; once the cancer cells fall off, the free cancer cells can It spreads throughout the body with blood or lymph fluid, forming metastases, which is life-threatening. At present, breast cancer has become a common tumor that threatens women's physical and mental health. [0003] Palbociclib is a new tar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCY02P20/55C07D471/04C07B2200/05
Inventor 吴豫生牛成山邹大鹏张森郭瑞云李敬亚
Owner TYK MEDICINES INC
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