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A kind of preparation method of JAK inhibitor momelotinib

An inhibitor and organic solvent technology, applied in the field of small molecule chemical drug preparation, can solve the problems of restricting the industrialized production of compounds, numerous reaction routes, complicated by-products, etc., and achieve the effects of low cost, simple process steps and high product purity

Active Publication Date: 2018-08-03
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Analyzing the above synthetic route, there are various reaction routes and complicated by-products greatly limit the industrial production of this compound

Method used

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  • A kind of preparation method of JAK inhibitor momelotinib
  • A kind of preparation method of JAK inhibitor momelotinib
  • A kind of preparation method of JAK inhibitor momelotinib

Examples

Experimental program
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Effect test

example 1

[0032] Preparation of intermediate C1

[0033]

[0034] Dissolve 1.78g (10mmol) of 4-morpholine-aniline and 1.7ml (20mmol) of 50% mononitrile amine aqueous solution in 50ml of absolute ethanol, add 1.5ml of concentrated hydrochloric acid dropwise, and heat to reflux at 80-90°C for 2h , and then add concentrated hydrochloric acid 1.5ml, continue to react for 8h. Concentrate to remove ethanol, add sodium carbonate aqueous solution to precipitate solid, filter, and wash the filter cake with acetone to obtain 2.3 g of white solid with a yield of 82%.

[0035] The data of the HNMR of target product intermediate C2 are as follows:

[0036] 1 H NMR (300MHz, DMSO-d6): δ7.16(brs, 2H), 6.88(m, 4H), 6.59(brs, 1H), 4.25(brs, 1H), 3.72(m, 4H), 3.04(m ,4H); 13 C NMR (75MHz, DMSO-d6): δ160.0, 154.9, 147.7, 124.7, 116.1, 66.1, 48.9.

Embodiment 2

[0038] Preparation of Intermediate C2

[0039]

[0040] 2g (10mmol) of methyl p-acetylbenzoate was added to 9ml (60mmol) of DMF-DMA solution, heated to reflux at 85°C for 15h, and filtered to obtain 2.3g of a yellow solid with a yield of 86%.

[0041] The data of the HNMR of target product intermediate C2 are as follows:

[0042] 1H NMR (300MHz, DMSO-d6): δ7.99(m, 4H), 7.76(d, J=12Hz, 1H), 5.84(d, J=12Hz, 1H), 3.88(s, 3H), 3.17( s, 3H), 2.94(s, 3H); 13 C NMR (75MHz, DMSO-d6): δ184.6, 165.8, 154.7, 144.2, 131.1, 128.9, 127.3, 91.0, 52.2, 44.5, 37.2.

Embodiment 3

[0044] Preparation of intermediate C4

[0045]

[0046] Add 1.68g (0.6mmol) of intermediate C1 (0.6mmol) and 1.16g (0.5mmol) of C2 to 35ml of n-butanol, then add 0.8g (10mmol) of sodium hydroxide, heat to 98°C for 24h under reflux, and get yellow after washing with ether solid. Dissolve 0.58 g of the obtained solid in 10 ml of acetone, add 0.12 g of lithium hydroxide in 1.6 ml of aqueous solution, react overnight at room temperature, concentrate to remove the organic solvent, adjust the pH to acidic with dilute hydrochloric acid, precipitate the solid, and filter to obtain intermediate C4 , two-step yield of 85%.

[0047] The data of the HNMR of target product intermediate C4 is as follows:

[0048] 1 H NMR (300MHz, DMSO-d6): δ9.45(s, 1H), 8.53(d, J=5.1Hz, 1H), 8.23(d, J=8.1Hz, 2H), 8.09(d, J=8.1 Hz, 2H), 7.67(d, J=8.7Hz, 2H), 7.37(d, J=5.1Hz, 1H), 6.93(d, J=8.7Hz, 2H), 3.75(m, 4H), 3.06( m,4H); 13 C NMR (75MHz, DMSO-d6): δ162.6, 160.3, 159.2, 146.2, 140.4, 132.8, 129...

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Abstract

The invention relates to a synthetic method of a JAK inhibitor Momelotinib, and belongs to the technical fields of pharmaceutical chemistry, chemical engineering and processes. The method includes (a) dissolving 4-morpholinoaniline and a cyanamide aqueous solution having a concentration of 50% into an organic solvent, adding concentrated hydrochloric acid dropwise, and heating and refluxing at 80-90 DEG C to obtain an intermediate C1, (b) heating and refluxing methyl 4-acetylbenzoate that is adopted as a raw material in a DMF-DMA solution to obtain an intermediate C2, (c) adding the intermediate C1 and the intermediate C2 into an organic solvent, adding sodium hydroxide, reacting under refluxing to obtain yellow solid C3, and hydrolyzing in a lithium hydroxide aqueous solution to obtain an intermediate C4, and (d) subjecting the intermediate C4 and aminoacetonitrile hydrochloride to amidation to obtain a target compound that is the Momelotinib. The method is easily available in raw material, simple in process, economical, environmental friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of preparation of small molecule chemical drugs, and more particularly designs a preparation method of Momelotinib, a kind of JAK inhibitor drug. Background technique [0002] Primary myelofibrosis (PMF), also known as myelofibroma, is a type of myeloproliferative neoplasm. Abnormal hematopoietic cell clones produce cytokines that cause the hematopoietic tissue in the bone marrow to be replaced by collagen fibers, resulting in the loss of the patient's ability to regenerate new blood cells. PMF can cause splenomegaly, cause hypersplenism, can cause pancytopenia, especially thrombocytopenia and anemia, and PMF can also cause other bone marrow malignancies. The quality of life of PMF patients is extremely poor, and they suffer from various symptoms all year round, and there is no very effective treatment. Recent studies have shown that PMF is closely related to abnormal regulation of JAK2-STAT signaling pathway, and J...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 王鹏顾月清黄锦鑫
Owner CHINA PHARM UNIV
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