The preparation method of the key intermediate 1 for the synthesis of baricitinib

A technology of baricitinib and intermediates, which is applied in the field of preparation of key intermediate 1, can solve the problems of high cost and cumbersome operation, and achieve the effects of low cost, simple purification and mild reaction conditions

Active Publication Date: 2020-03-20
海化生命(厦门)科技有限公司
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Problems solved by technology

Therefore, these two routes are costly and cumbersome in the preparation of key intermediate 1

Method used

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  • The preparation method of the key intermediate 1 for the synthesis of baricitinib
  • The preparation method of the key intermediate 1 for the synthesis of baricitinib
  • The preparation method of the key intermediate 1 for the synthesis of baricitinib

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preparation example Construction

[0030] A preparation method for the key intermediate 1 of baricitinib synthesis, which comprises the following steps:

[0031] (1) Synthesis of intermediate B: 1,3-dibromo-2,2-dimethoxypropane (SM), ethanesulfonamide (SM2) reacted with ring-closing reaction under alkaline conditions, and then under acidic conditions Next, acetal deprotection obtains intermediate B, and the structural formula of said intermediate B is:

[0032]

[0033] (2) Synthesis of the key intermediate 1: the intermediate B obtained in step (1) is reacted with diethyl cyanomethylphosphonate under alkaline conditions to obtain the key intermediate 1, the key intermediate 1 The structural formula is:

[0034]

[0035] Wherein, the specific operation method of step (1) is: under the protection of nitrogen, add ethanesulfonamide, alkaline reagent A and organic solvent A into the reaction flask, stir for 30-40min; then add 1,3-dibromo-2 , 2-dimethoxypropane (SM), stirred for 30-40min; then the reaction ...

Embodiment 1

[0046] 1.1 Synthesis of Intermediate B

[0047]Under the protection of nitrogen, in a 5L three-necked flask, add the starting materials ethanesulfonamide (163.5g, 1.5mol), anhydrous potassium carbonate (275.8g, 2.0mol) and anhydrous DMF (1L), stir for 30min, then add 1,3-dibromo-2,2-dimethoxypropane (SM) (259.9g, 1.0mol), stirred for 30min, then raised the temperature of the reaction system to 95-100°C, and reacted at this temperature for 20-22h , and then cooled to room temperature. Afterwards, use 0.1N HCl to adjust the pH to 2~3, and stir thoroughly under this condition for 2-3h, then add 2L of water to the system, and a large amount of off-white solid precipitates, which is filtered and dried to obtain 134.1g of solid, with a yield of 82.3 %.

[0048] NMR analysis:

[0049] 1 H-NMR (400MHz, DMSO-d6): 5.12(m,2H), 5.08(m,2H), 3.12(q,2H), 1.44(t,3H).

[0050] 1.2 Synthesis of key intermediate 1

[0051] Under the protection of nitrogen, add diethyl cyanomethylphosphonat...

Embodiment 2

[0055] 2.1 Synthesis of Intermediate B

[0056] Under nitrogen protection, in a 5L three-necked flask, add the starting materials ethanesulfonamide (163.5g, 1.5mol), anhydrous potassium carbonate (275.8g, 2.0mol) and anhydrous THF (1L), stir for 30min, and then add SM (259.9g, 1.0mol), stirred for 30min; then the reaction system was heated up to 60-65°C, and reacted for 35-40h under this temperature condition; then cooled to room temperature, adjusted to PH=4~5 with 0.1N HCl, in Stir well under this condition for 2-3h; then add 2L of water to the system, a large amount of off-white solid precipitates, filter and dry to obtain 96.5g of solid with a yield of 59.2%.

[0057] 2.2 Synthesis of key intermediate 1

[0058] Under nitrogen protection, in a 3L three-necked flask, add diethyl cyanomethylphosphonate (265.6g, 1.5mol) and anhydrous DMF (300ml), stir to dissolve; then lower the system temperature to -10~0℃ , under this condition, slowly add THF (200ml) solution containing ...

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Abstract

The invention relates to a preparation method for synthesizing a key intermediate 1 of Baricitinib. The preparation method comprises the following steps: generating ring closing reaction by virtue of1,3-dibromo-2,2-dimethoxypropane (SM) and ethyl sulfonamide (SM2) under an alkaline condition, and carrying out acetal deprotection under an acidic condition, so as to obtain an intermediate B; and generating witting reaction by virtue of the obtained intermediate B and diethyl cyanomethylphosphonate under the alkaline condition, so as to obtain the key intermediate 1. According to the preparationmethod, the ring closing reaction is generated by virtue of the commercial materials SM and ethyl sulfonamide under the alkaline condition, acetal deprotection is carried out under the acidic condition so as to obtain intermediate B, and witting reaction is carried out so as to obtain the key intermediate 1; the key intermediate 1 can be actually obtained only through two synthetic steps; and compared with the prior art, the preparation method has the advantages that the synthetic route is greatly shortened, the hydrogenation is avoided, and the production cost of the key intermediate 1 is lowered.

Description

technical field [0001] The present invention relates to a preparation method for the key intermediate 1 used in the synthesis of baricitinib. Background technique [0002] Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and progressive destruction of joints. There are more than 23 million RA patients worldwide, and the disease affects about three times as many women as men. Both patients and physicians say there are still significant opportunities to improve patient care. Current RA treatment includes the use of non-steroidal anti-inflammatory drugs, oral disease-modifying drugs such as methotrexate, and injectable biologics that selectively target biotransmitters involved in the pathogenesis of RA, such as adalimumab. However, because the price of biological agents is quite expensive, it is only suitable for a small number of groups, so oral chemical drugs are the mainstream drugs for the treatment of RA. [0003] Baricitinib is a s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/06
CPCC07D205/06
Inventor 钟宝香邱炳林陈华栋李金林黄志征
Owner 海化生命(厦门)科技有限公司
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