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Method for synthesizing tert-butyl N-[(3R, 6R)-6-methylpiperidine-3-yl] carbamate by chemical enzyme method

A technology of methylpiperidine and chemical enzymatic method, which is applied in the field of synthesis of chiral drug intermediates, can solve the problems of difficult synthesis of starting materials, high production costs, long steps, etc., achieve good industrial synthesis application prospects, and reduce reaction steps , the effect of mild reaction conditions

Pending Publication Date: 2021-06-01
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthetic route has long steps and requires the use of sodium azide, which is highly toxic and explosive, and the synthesis of starting materials is difficult. It needs to be synthesized in multiple steps and separated by chiral SFC, and the production cost is high.

Method used

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  • Method for synthesizing tert-butyl N-[(3R, 6R)-6-methylpiperidine-3-yl] carbamate by chemical enzyme method
  • Method for synthesizing tert-butyl N-[(3R, 6R)-6-methylpiperidine-3-yl] carbamate by chemical enzyme method
  • Method for synthesizing tert-butyl N-[(3R, 6R)-6-methylpiperidine-3-yl] carbamate by chemical enzyme method

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Embodiment 1

[0036] The method for synthesizing tert-butyl N-[(3R,6R)-6-methylpiperidin-3-yl]carbamate by chemical enzymatic method provided in this embodiment comprises the following steps:

[0037] S1. Preparation of enzyme-catalyzed substrate: Dissolve 60g of Boc-D-ethyl pyroglutamate in 1000mL of anhydrous tetrahydrofuran, replace with nitrogen for 3 times, then cool down to -10-0°C, and add 300mL of methyl Magnesium halide tetrahydrofuran solution, continue to stir at -10-0°C for 1 hour after dropping, then raise the temperature to 5-10°C to continue the reaction for 6 hours. After the reaction was completed, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was slurried with n-hexane, filtered and dried to obtain 54.17 g of enzyme-catalyzed Substrate; Wherein, the structural formula of enzyme cat...

Embodiment 2-6

[0044]In order to further verify the influence of the type of aminotransferase on the conversion rate of lactam and ee value in step S2, repeat the synthetic method of Example 1 according to the type of aminotransferase in Table 1, other unlisted components, contents and reaction conditions All are exactly the same as in Example 1, the corresponding lactams are respectively obtained, and the conversion rate and ee value of the lactams are calculated.

[0045] Table 1:

[0046]

[0047]

[0048] From the data in Table 1, it can be seen that the conversion rate and ee value of the lactam produced by using different types of aminotransferases are different. Among them, when the aminotransferase is SCUT-ATA-01, the lactam The conversion rate is as high as 99.91%, and the ee value is greater than 99.9%.

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Abstract

The invention relates to a method for synthesizing tert-butyl N-[(3R, 6R)-6-methylpiperidine-3-yl] carbamate by a chemical enzyme method, which comprises the following steps: S1, taking Boc-D-ethyl pyroglutamate as a substrate, and reacting with methyl magnesium halide at the temperature of -10- 0 DEG C to obtain an enzyme catalysis substrate; S2, adding an enzyme catalysis substrate into a potassium phosphate buffer solution containing an amino donor, then adding pyridoxal phosphate and transaminase, and carrying out spontaneous in-situ cyclization reaction to obtain lactam with double chiral centers; S3, lactam being subjected to a reduction reaction, and obtaining N-[(3R, 6R)-6-methylpiperidine-3-yl] tert-butyl carbamate. According to the method, Boc-D-ethyl pyroglutamate is taken as a raw material, so that the reaction steps are reduced, the reaction conditions are milder, an expensive metal catalyst and a high-pressure condition are not needed, the reaction process is safer, meanwhile, a complicated racemate resolution process is avoided, and the production cost is reduced.

Description

technical field [0001] The invention relates to the technical field of synthesis of chiral drug intermediates, in particular to a method for synthesizing tert-butyl N-[(3R,6R)-6-methylpiperidin-3-yl]carbamate by chemical enzymatic method. Background technique [0002] Orexin receptor antagonists can be used to treat insomnia in adults, and IRAK4 inhibitors can be used to treat various inflammatory-related diseases; and chiral piperidinamine compounds: N-[(3R,6R)-6-methyl Basepiperidin-3-yl] tert-butyl carbamate has important production significance as an important intermediate for the synthesis of orexin (Orexin) receptor antagonists and IRAK4 inhibitors. [0003] The synthetic route of existing N-[(3R,6R)-6-methylpiperidin-3-yl] carbamate tert-butyl ester has following several kinds at present: [0004] Patent WO2010048012A discloses a synthesis method of N-[(3R,6R)-6-methylpiperidin-3-yl]carbamate tert-butyl ester, the specific synthesis route is as follows: [0005] ...

Claims

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Application Information

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IPC IPC(8): C12P17/12C07D211/56
CPCC12P17/12C07D211/56Y02P20/55
Inventor 李彤李杉张雷
Owner SOUTH CHINA UNIV OF TECH
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