Synthesis method of lifitegrast intermediate

A technology of rifemilast and synthetic method, which is applied in the field of chemical pharmacy, can solve problems such as unstable process, slow reaction speed, difficult post-processing, etc., and achieve the effects of strong process controllability, reduced amount of impurities, and widened range

Inactive Publication Date: 2018-03-30
成都惟邦药业有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0007] The main disadvantages of this route are: (1) The safety of large-scale production is poor: when excessive carbon dioxide is introduced at extremely low temperature, the risk of blowout will be caused by the rapid gasification of carbon dioxide during post-processing, which will bring safety hazards to large-scale production ; The carbon dioxide introduced should not only be excessive, but also need to go through the water removal process, which is not easy to operate and has poor repeatability, so it is not suitable for commercial scale production
(2) The whole reaction is not easy to monitor: in the synthesis of LIFI-015 to LIFI-006, when carbon dioxide is introduced to generate acid, the reaction speed between the formed intermediate and LIFI-015 is slow, and the reaction speed of LIFI-015 and LIFI-006 in HPLC In the case of central control, it is easy to remove the Trt group and cannot be accurately quantified, and the entire reaction process cannot be monitored, making the process unstable, commercial production yield unstable, and high risk
(3) High cost and insufficient atom economy: In this process, if LIFI-015 cannot be completely converted into acid, a large amount of impurities remain in LFI-006, which is difficult for post-processing, resulting in unqualified products
Moreover, because the molecular weight of the Trt group is too large, the atom economy of the reaction is insufficient, and the production cost is high

Method used

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  • Synthesis method of lifitegrast intermediate
  • Synthesis method of lifitegrast intermediate
  • Synthesis method of lifitegrast intermediate

Examples

Experimental program
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Embodiment 1

[0040] Embodiment 1, the preparation of rifemilast intermediate of the present invention

[0041] (1) Synthesis of benzyl 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0042] In a 5L reactor, under mechanical stirring, sequentially add 1.20kg of tetrahydrofuran, 200g of 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline and N,N,N , N-tetramethylethylenediamine 100g, nitrogen gas was passed into the reaction kettle for 15min to exhaust the air. Cool down the reactor system to -75~-78°C. Add 300ml of 2.5M n-butyllithium solution dropwise and control the rate of addition to maintain the internal temperature at -70°C to -78°C. After the dropwise addition, keep at -70°C to -78°C for 1h. Add 120g of benzyl chloroformate dropwise, control the feed rate to keep the internal temperature not exceeding -70°C, monitor the reaction by HPLC method, after the reaction is complete, add saturated ammonium chloride water to the reaction syst...

Embodiment 2

[0053] Embodiment 2, the preparation of rifemilast intermediate of the present invention

[0054] (1) Synthesis of benzyl 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0055] In a 10L reactor, under mechanical stirring, 2.6kg tetrahydrofuran, 400g 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline and 240g N,N, N,N-Tetramethylethylenediamine, blow nitrogen into the reaction kettle for 20 minutes to exhaust the air. Cool down the reactor system to -75~-78°C. Add 600ml of 2.5M n-butyllithium solution dropwise and control the rate of addition to keep the internal temperature at -70°C to -78°C. After the dropwise addition, keep at -70°C to -78°C for reaction. 250 g of benzyl chloroformate was added dropwise, and the feed rate was controlled to keep the internal temperature not exceeding -70°C. The reaction was monitored by HPLC. After the reaction was complete, add saturated ammonium chloride water to the reaction system to qu...

Embodiment 3

[0060] Embodiment 3, the preparation of rifemilast intermediate of the present invention

[0061] (1) Synthesis of benzyl 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

[0062] In a 50L reactor, under mechanical stirring, 11.8kg of tetrahydrofuran, 1.70kg of 5,7-dichloro-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline and N,N, N,N-Tetramethylethylenediamine 0.85kg, feed nitrogen into the reaction kettle for 25min to exhaust the air. Cool down the reactor system to -75~-78°C. Add 2.71 L of 2.5M n-butyllithium solution dropwise and control the rate of addition to maintain the internal temperature at -70°C to -78°C. After the dropwise addition is complete, keep the reaction below -70°C to -78°C. Add 1.16 kg of benzyl chloroformate, and control the feed rate to keep the internal temperature not exceeding -70°C. The reaction is monitored by HPLC method. After the reaction is complete, add saturated ammonium chloride water to the reaction s...

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Abstract

The invention discloses a preparation method of a lifitegrast intermediate. The preparation method comprises the following steps: (1) taking a compound (1), treating the compound (1) by using tetramethyldiethylamine and n-butyl lithium, adding benzyl chloroformate, reacting at the temperature of 70 DEG C below zero to obtain a compound (2); and (2) taking the compound (2), reacting the compound (2) with a strong alkaline solution, adjusting pH to be 3-4 after the reaction is ended, and extracting to obtain a compound (3). The prepared lifitegrast intermediate is high in process selectivity, high in controllability, high in stability and high in total yield, and is suitable for commercial large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing a rifelast intermediate, belonging to the field of chemical pharmacy. Background technique [0002] Dry eye disease refers to the general term for various diseases that cause tear quality or quantity abnormality or dynamic abnormality caused by any reason, resulting in decreased stability of tear film, accompanied by ocular discomfort and ocular surface tissue lesions. Common symptoms include dry eyes, tiredness, itching, foreign body sensation, photophobia, etc.; in more severe cases, the eyes will be red, swollen, hyperemic, keratinized, etc., which can cause keratoconjunctival lesions, affect vision, and lead to irreversible decline in vision . [0003] In July 2016, the FDA officially approved the application of the new drug lifitegrast eye drops, which acts by antagonizing the combination of ICAM-1 and LFA-1, and has obvious curative effect on dry eye disease with a low incidence of adverse rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/06
CPCC07D217/06
Inventor 随裕敏陈志勇敬方梨
Owner 成都惟邦药业有限公司
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