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Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine

A cyclohexanediamine, chiral technology, applied in the field of preparation of chiral N-Boc-trans-1,2-cyclohexanediamine, can solve problems such as disadvantages, and achieve the effect of avoiding selectivity problems

Active Publication Date: 2022-02-01
BENGBU CHINA SYNCHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Obviously this is not conducive to the full reaction of expensive raw materials (1R,2R)-1,2-cyclohexanediamine or (1S,2S)-1,2-cyclohexanediamine

Method used

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  • Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine
  • Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine
  • Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] Put 7-azabicyclo[4.1.0]heptane (97.2 g, 1.0 mol), DMAP 2.2 g, and di-tert-butyl dicarbonate (261.9 g, 1.2 mol) in 600 mL of dichloromethane into the reaction flask. Control the temperature at 0-5°C, add triethylamine (126.5g, 1.25mol) dropwise, and naturally raise the temperature to room temperature to react for 8 hours after dropping, TLC detects that the reaction is complete, adjust the pH=7-8 with 1M hydrochloric acid to separate layers, dichloromethane 400mL Extract, combine the organic phases, wash with 200mL of 20% potassium bisulfate aqueous solution, wash with saturated sodium carbonate aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and distill under reduced pressure at 55-60°C to obtain 7-azabicyclo[4.1.0]heptane 182.1 g of tert-butyl alkane-7-carboxylate, yield 92.2%, chemical purity 99.4%. 1 HNMR (400MHz, CDCl3): 4.12-4.10(m, 2H), 1.74-1.46(m, 4H), 1.44(s, 9H), 1.21-1.10(m, 4H).

Embodiment 2

[0026]

[0027] Add 98.7g (0.5mol, 1eq) of tert-butyl 7-azabicyclo[4.1.0]heptane-7-carboxylate, 500mL of 25% ammonia water and 4.4g of triphenylboron into the autoclave, and mix well. . The temperature was raised to 95-100° C., and the pressure in the kettle was 0.8 MPa to react for 5 hours. Cool down to room temperature, concentrate to dryness under reduced pressure, add 400 mL of dichloromethane and 200 mL of 20% ammonium chloride solution for washing, extract the aqueous phase with 200 mL of dichloromethane, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, and concentrate under reduced pressure. After adding n-heptane and cooling down to 10°C, a solid precipitated out. After filtration, 96.9 g of N-Boc-trans-1,2-cyclohexanediamine was obtained, with a yield of 90.4% and a chemical purity of 99.0%. 1 H NMR (400MHz, CDCl3): 4.51(s, 1H), 3.12(dt, J=4.0, 10.8Hz, 1H), 2.33(dt, J=4.0and J=10.8Hz, 1H), 1.84-2.02(m , 2H), 1.68-1.72(m, 2H), 1.51...

Embodiment 3

[0029]

[0030] Add N-Boc-trans-1,2-cyclohexanediamine (85.7g, 0.4mol), (S)-3-cyclohexenecarboxylic acid (49.5g, 0.392mol) and 600mL of 2-methyl Tetrahydrofuran, mix evenly and heat up to 70-75°C, react for 3-5 hours after the reaction solution is dissolved, cool down to 10-15°C with a gradient (10°C / 30min), filter, and rinse the filter cake with 2-methyltetrahydrofuran, (S)-3-cyclohexenecarboxylic acid / N-Boc-(1S,2S)-1,2-cyclohexanediamine salt is obtained, and the filtrate is to be recovered. Then put it back into the kettle, add 300mL of dichloromethane, add dropwise 20% aqueous sodium hydroxide solution to adjust the pH=11-12, separate layers, extract the aqueous phase with 150mL of dichloromethane, extract 3 times in total, combine the organic phases, anhydrous sulfuric acid Dry over sodium, concentrate under reduced pressure, add n-heptane to cool down to 10°C, solids precipitate out, filter to obtain 36.7g of N-Boc-(1S,2S)-1,2-cyclohexanediamine, yield 85.6%, GC99.7 ...

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Abstract

The invention discloses a preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking 7-azabicyclo [4.1.0] heptane as a raw material, and reacting the 7-azabicyclo [4.1.0] heptane with dicarbonyl di-tert-butyl ester under an alkaline condition to generate N-Boc-7-azabicyclo [4.1.0] heptane 2; then carrying out ring opening on the N-Boc-7-azabicyclo [4.1.0] heptane 2 and ammonia water at high temperature and high pressure to obtain N-Boc-trans-1, 2-cyclohexanediamine 3; adopting (S)-3-cyclohexenecarboxylic acid for salifying resolution, and obtaining the N-Boc-(1S, 2S)-1, 2-cyclohexanediamine through dissociation. The method is simple and convenient in reaction operation and relatively simple in steps, and a resolving agent can be recycled and reused, so that the method has a potential industrial amplification prospect.

Description

technical field [0001] The invention relates to a preparation method of chiral N-Boc-trans-1,2-cyclohexanediamine, belonging to the technical field of organic synthesis. Background technique [0002] Trans-1,2-cyclohexanediamine has C2 symmetry. As a heterocyclic chiral organic amine with symmetrical structure, it is widely used in the field of medicine. It is an important pharmaceutical intermediate and plays an important role in chemical linkage. Chiral compounds have been shown to bind biologically important molecules. [0003] N-Boc-trans-1,2-cyclohexanediamine is a good solution to one of the amino group reaction selection problems. N-Boc-trans-1,2-cyclohexanediamine is further divided into N-Boc-1S,2S-1,2-cyclohexanediamine and N-Boc-1R,2R-1,2-cyclohexanediamine diamine. Among them, N-Boc-(1S,2S)-1,2-cyclohexanediamine can also be applied to the synthesis of sterically hindered anti-tumor platinum (II) complexes, N-Boc-trans-1,2-cyclohexanediamine Amines can coordi...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C269/08C07C271/24C07D203/26C07C51/41C07C61/22
CPCC07C269/06C07C269/08C07D203/26C07C51/412C07C2601/14C07C2601/16C07B2200/07C07C271/24C07C61/22Y02P20/55
Inventor 刘洪强杨忆魏佳玉朱克明王松松年成成
Owner BENGBU CHINA SYNCHEM TECH CO LTD
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