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Preparation method of anaplastic lymphoma kinase inhibitor

A technology of an intermediate and a palladium catalyst is applied in the field of preparation of anaplastic lymphoma kinase inhibitors, and can solve the problems of long synthesis route, unsuitable for industrial production, complicated reaction operation and the like

Active Publication Date: 2017-09-26
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The synthesis of compounds of formula (I) was first disclosed in the document WO2012092880A1, but the synthesis method in this document has the disadvantages of long synthetic route, low reaction yield, complicated reaction operation, etc., and many intermediate compounds need to be carried out by column chromatography. Separation, not suitable for industrial production

Method used

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  • Preparation method of anaplastic lymphoma kinase inhibitor
  • Preparation method of anaplastic lymphoma kinase inhibitor
  • Preparation method of anaplastic lymphoma kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1: Synthesis of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (Compound 2)

[0124]

[0125] Add compound 1 (21kg, 165mol), anhydrous sodium acetate (14.91kg, 181.8mol) and water (100L) into a 500L reactor, and raise the temperature to 70-75°C. Chloroacetaldehyde (49 kg, 40% aqueous solution, 249.7 mol) was added dropwise. After dropping, the temperature was raised to 90° C. to react for 3.5 hours, cooled to room temperature, and the reaction solution was centrifuged, washed with water, and dried to obtain 22.8 kg of brown powder as Compound 2 with a yield of 91.6%.

[0126] 1 H NMR (400MHz, DMSO-d 6): δ11.39 (1H, br), 11.05 (1H, br), 10.43 (1H, br), 6.53-6.54 (1H, d, J=5.2Hz), 6.18-6.19 (1H, d, J=5.2 Hz).

Embodiment 2

[0127] Example 2: Synthesis of 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diol (compound 3)

[0128]

[0129] Add compound 2 (20.5 kg, 135.6 mol) and trifluoroacetic acid (205 kg, 1797 mol) into a 500 L reactor from the upper port of the reactor, stir and mix well. The temperature was lowered to 0-5°C, and triethylsilane (37.9kg, 325mol) was added dropwise. After dropping, restore the temperature to 10-30°C and react overnight. Trifluoroacetic acid was evaporated under reduced pressure, 100kg of petroleum ether was added into the kettle, stirred, centrifuged, and the filter cake was dried to obtain 27.9kg of trifluoroacetic acid salt of compound 3 as a brown solid, with a yield of 77%.

[0130] 1 H NMR (400MHz, DMSO-d 6 ): δ11.07(1H, br), 10.48(1H, br), 10.06(1H, br), 3.49-3.53(2H, t, J=18Hz), 2.58-2.63(2H, t, J=18Hz) .

Embodiment 3

[0131] Example 3: Synthesis of 2,4-dichloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (compound 4)

[0132]

[0133] Add the trifluoroacetate (19.0kg, 71.1mol) of compound 3 obtained above into a 500L reactor, add phosphorus oxychloride (218kg, 1422mol), seal the above system and stir evenly, drop diiso Propylethylamine (32.2kg, 248mol) was added dropwise, heated to reflux overnight (about 12 hours). Phosphorus oxychloride was distilled off under reduced pressure, and a mixture of 150 L of water and 500 kg of ice was added to the residue with constant stirring to precipitate a solid, which was centrifugally filtered to obtain 4.05 kg of compound 4 as yellow crystals, with a yield of 30%.

[0134] 1 H NMR (400MHz, DMSO-d 6 ): δ6.45 (1H, br), 3.81-3.85 (2H, d, J=8.8Hz), 3.10-3.14 (2H, d, J=8.8Hz).

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Abstract

The invention discloses a method for preparing a compound as shown in a formula (I), an intermediate compound as shown in a formula (II) and used for preparing the compound as shown in the formula (I), a compound as shown in a formula (III) and a preparation method of the compound as shown in the formula (III). The compound as shown in the formula (I) is the anaplastic lymphoma kinase inhibitor, and it has proved that the anaplastic lymphoma kinase inhibitor can inhibit related diseases such as a non-small cell lung cancer.

Description

technical field [0001] The invention discloses a preparation method of an anaplastic lymphoma kinase (Anaplastic Lymphoma Kinase, ALK) inhibitor. The invention also relates to the intermediates required for the preparation of such inhibitors and the synthesis of the required intermediates. Background technique [0002] The compound of formula (I) is a small molecule anaplastic lymphoma kinase (Anaplastic Lymphoma Kinase, ALK) inhibitor. Anaplastic lymphoma kinase (ALK) is a member of the insulin-like growth factor receptor tyrosine kinase family. Its expression is closely related to the development of brain tissue. Its abnormal activation is related to the development of non-small cell lung cancer and neuroblastoma. There is a very close relationship between occurrence and development. The mechanism of abnormal activation of ALK includes gain of function caused by point mutation, ALK gene reassignment, formation of ALK fusion gene and production of cancerous fusion protein...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D211/58
CPCC07D211/58C07D487/04Y02P20/55
Inventor 杨利民张传玉韩军儒孙德广冀冲张晓军韩永信
Owner SHOUYAO HLDG BEIJING CO LTD
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