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Preparation method of N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine

A technology of fluorene methoxycarbonyl and tert-butoxycarbonyl, applied in the field of organic synthesis, can solve problems such as being unsuitable for scale-up production, and achieve the effects of mild reaction conditions and concise synthesis route

Inactive Publication Date: 2018-08-10
JIANGSU GENSCRIPT BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No matter from safety or cost considerations, this synthetic route is not suitable for scale-up production

Method used

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  • Preparation method of N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine
  • Preparation method of N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine
  • Preparation method of N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In a 5.0L glass reaction flask, add Nα-fluorenylmethoxycarbonyl-lysine hydrochloride (200g, 0.5mol), N, N-diisopropylethylamine (DIEA) (258g, 2.0mol) successively and methanol (2.0 L). Stir at room temperature until clarification, at 0°C, slowly add trityl chloride (278g, 1.0mol) in tetrahydrofuran (1.0L) dropwise to the reaction solution, add about 1.0h, continue to react at 0°C for 2.0h, then The reaction was carried out at room temperature for 6.0 h, and HPLC detection showed that the raw materials had reacted completely. Concentrate under reduced pressure to remove the solvent, the crude product is separated with methanol and n-hexane, the methanol phase is washed 6-8 times with n-hexane, the methanol phase is concentrated, the crude product is extracted with ethyl acetate, washed with saturated brine, and the organic phase is evaporated to dryness to obtain a gray Crude solid.

[0026] The above gray solid was dissolved in 1.5L of methanol, 50ml (0.62mol) of 37% ...

Embodiment 2

[0030] In a 5.0L glass reaction flask, Nα-fluorenylmethoxycarbonyl-lysine hydrochloride (200g, 0.5mol), DIEA (387g, 3.0mol) and methanol (2.0L) were added sequentially. Stir at room temperature until clarification, at 0°C, slowly add trityl chloride (361g, 1.3mol) in tetrahydrofuran (1.5L) dropwise to the reaction solution, add about 1.0h, continue to react at 0°C for 2.0h, then The reaction was carried out at room temperature for 6.0 h, and HPLC detection showed that the raw materials had reacted completely. Concentrate under reduced pressure to remove the solvent, the crude product is separated with methanol and n-hexane, the methanol phase is washed 6-8 times with n-hexane, the methanol phase is concentrated, the crude product is extracted with ethyl acetate, washed with saturated brine, and the organic phase is evaporated to dryness to obtain a gray Crude solid.

[0031] The above gray solid was dissolved in 1.5L methanol, 50ml (0.62mol) of 37% formaldehyde solution and s...

Embodiment 3

[0035] In a 5.0L glass reaction flask, Nα-fluorenylmethoxycarbonyl-lysine hydrochloride (200g, 0.5mol), DIEA (387g, 3.0mol) and methanol (2.0L) were added sequentially. Stir at room temperature until clear. At 0°C, slowly add 2-chlorotrityl chloride (406g, 1.3mol) in tetrahydrofuran (1.0L) dropwise to the reaction solution. After about 1.0h, continue to react at 0°C for 2.0 h, and then reacted at room temperature for 6.0 h, and HPLC detection showed that the raw materials had reacted completely. Concentrate under reduced pressure to remove the solvent, the crude product is separated with methanol and n-hexane, the methanol phase is washed 6-8 times with n-hexane, the methanol phase is concentrated, the crude product is extracted with ethyl acetate, washed with saturated brine, and the organic phase is evaporated to dryness to obtain a gray Crude solid.

[0036] The above gray solid was dissolved in 1.5L of methanol, 60ml (0.74mol) of 37% formaldehyde solution and sodium cyano...

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Abstract

The invention discloses a preparation method of N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine. The preparation method comprises the following steps: taking N alpha-fluorenylmethoxycarbonyl-lysine hydrochloride as a raw material, performing alkylation with halide (R-X) under alkaline conditions, performing reductive amination on alkylate in an aqueous formaldehyde solution to introduce methyl, removing an R group of a reductive amination product under acidic conditions, then introducing a t-butyloxycarboryl (BOC) protecting group under alkaline conditions and performing re-crystallization treatment to obtain a product. The preparation method disclosed by the invention is simple in synthetic route and mild in reaction conditions, and the next-step reaction can be directly carried out after an intermediate is simply washed and concentrated. The reaction yield in each step is close to quantification, the total yield can reach above 80 percent, the purity of a final product exceeds 98 percent, and a safe and efficient synthetic route is provided for the preparation of the N epsilon-tert-butoxycarbonyl-N alpha-fluorenylmethoxycarbonyl-N epsilon-methyl-lysine.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of Nε-tert-butoxycarbonyl-Nα-fluorenylmethoxycarbonyl-Nε-methyl-lysine. Background technique [0002] Methylation is an important modification of proteins and nucleic acids, and lysine methylation is a relatively stable post-translational modification that can regulate the functions of various proteins. Methylation of histone or non-histone lysine can promote cell proliferation, inhibit tumor cell growth, regulate gene expression, and affect DNA replication and repair. Nε-tert-butoxycarbonyl-Nα-fluorenylmethoxycarbonyl-Nε-methyl-lysine is an important amino acid raw material and a reagent often used in the field of peptide synthesis. [0003] Existing synthetic technology such as literature: Synthetic Chemistry, 2009; 17, 216-219, is based on Nα-benzylmethoxycarbonyl lysine as raw material, the terminal amino group is protected with trifluoroacetyl, and reac...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/04C07C231/12C07C233/63
CPCC07C231/12C07C269/04C07C233/63C07C271/22Y02P20/55
Inventor 沈军伟张建齐罗福林
Owner JIANGSU GENSCRIPT BIOTECH CO LTD
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