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A preparing method of GLYX-13 and a compound used for preparing the GLYX-13

A compound and condensing agent technology, which is applied in the field of compound preparation of GLYX-13, can solve the problems of low synthesis yield, low yield, and difficult removal, etc., and achieve simple post-production treatment, high yield selectivity, and easy removal Effect

Active Publication Date: 2017-12-15
NHWA PHARMA CORPORATION +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007]①Intermediate IV is also difficult to obtain, and the yield is low. Even if it is obtained, it is an oily substance, which is inconvenient for the next step of reaction feeding
[0008] ② The synthetic yield of intermediate V is low, the reaction is incomplete, and there are by-products that are difficult to remove. The main reason is that the unsuitable condensation method isobutyl chloroformate IBCF , and the raw material proline methyl ester hydrochloride used is extremely hygroscopic, which is inconvenient for feeding operation
[0009]③ During the synthesis of intermediate VI, the compatibility between different protecting groups was not considered, and the Fmoc protecting group would be removed during the reaction, resulting in the yield of intermediate VI very low
[0010]④ Although the method of removing the Fmoc protecting group is classic, if it is to be applied to process scale-up research, the feasibility is very poor, because DMF and piperidine have high boiling points and high viscosity. In addition, it has a significant impact on the subsequent peptide condensation reaction, and piperidine is a precursor drug that is controlled and difficult to purchase
[0011]⑤The method of intermediate VIII de-tert-butyl is also very classic, the reagent used is trifluoroacetic acid, but trifluoroacetic acid is highly corrosive, volatile and toxic Large, not suitable for industrial production, and difficult to remove after treatment

Method used

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  • A preparing method of GLYX-13 and a compound used for preparing the GLYX-13
  • A preparing method of GLYX-13 and a compound used for preparing the GLYX-13
  • A preparing method of GLYX-13 and a compound used for preparing the GLYX-13

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Effect test

Embodiment 1

[0052] The preparation of embodiment 1 intermediate I

[0053]

[0054]Add N-Cbz-L-threonine amide (2mol, 504g), palladium carbon (50.4g) and anhydrous methanol 3000mL in the autoclave of 5L, mechanical stirring makes N-Cbz-L-threonine amide dissolve, to The reactor was fed with hydrogen to maintain the pressure at 1 MPa, and reacted at room temperature for 12 hours. After the reaction was completed, the palladium carbon was removed by filtration, and the solvent was removed from the filtrate with a rotary evaporator to obtain a crude product of light yellow oil. The crude product was dissolved in 2L of acetone, and a solution of hydrogen chloride in isopropanol was added dropwise in an ice-water bath to precipitate a white solid, which was filtered by suction and vacuum-dried to obtain 289 g of white solid powder, yield: 93%. 1 H NMR (400MHz,D 2 O)δ4.15(p,J=6.1Hz,1H),3.86(d,J=5.2Hz,1H),1.25(d,J=6.5Hz,3H).HRMS(ESI-TOF+)m / z Calcd .forC 4 h 11 N 2 o 2 + [M+H] + :119....

Embodiment 2

[0055] The preparation of embodiment 2 intermediate II

Embodiment 21

[0057]

[0058] Add N-Fmoc-proline (1.5mol, 505g) to a 3L four-necked flask, add 1500mL anhydrous DMF under the condition of nitrogen flow, mechanical stirring makes it dissolve and adds N-methylmorpholine (152g), Make the bottom of the reaction bottle in a low-temperature reactor, slowly add isobutyl chloroformate (205g) dropwise and maintain the temperature of the reaction solution below -15°C, add intermediate I (243g) in solid form after the dropwise addition, and then slowly N-methylmorpholine (152 g) was added dropwise, and the reaction solution was gradually returned to room temperature after the dropwise addition was completed. The reaction solution was transferred to a plastic bucket and purified water (9 L) was added, and 1500 mL of ethyl acetate was added dropwise thereto under the condition of mechanical stirring, a white solid was precipitated, filtered by suction and vacuum-dried to obtain 585 g of a white solid, yield: 89.2%. 1 H NMR (400MHz, DMSO-d 6 )δ7.9...

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Abstract

The invention belongs to the field of medicine compounds, and provides a preparing method of GLYX-13 and a compound used for preparing the GLYX-13. Fmoc-O-tert-butyl-L-threonine, Fmoc-L-proline, N-carbobenzyloxy-L-threoninamide and proline benzyl ester hydrochloride are adopted as initial raw materials of the method. By adoption of the method, the GLYX-13 can be prepared in a high yield in an industrial scale through eight easy and economical synthetic steps, the GLYX-13 can be prepared through simple process operation in a good yield and at a low cost without the need of utilizing expensive peptide condensation agents or controlled, precursor-chemical or highly corrosive deprotection agents.

Description

technical field [0001] The invention belongs to the field of pharmaceutical compounds and provides a preparation method of GLYX-13 and a compound used for preparing GLYX-13. Background technique [0002] Rapastinel (GLYX-13) is a new antidepressant drug candidate developed by Naurex, a small American biotechnology company. It is a partial agonist at the glycine site of the N-methyl-D-aspartate receptor. The structure is shown below. It is a Tetrapeptide derivative, very soluble in water. Due to its rapid-onset antidepressant effect in the early stage of research and development, it has obtained fast-track approval from the US FDA and has entered the phase III clinical research stage. [0003] [0004] Disclosed in CN104109189A is the synthetic technique research of GLYX-13, and this route takes Fmoc-O-tert-butyl-L-threonine, Fmoc-proline and proline methyl ester hydrochloride as starting materials, using chlorine Isobutyl formate was used as the condensation reagent, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/06
CPCC07K5/1013Y02P20/55
Inventor 刘经建张亮仁张桂森王国海
Owner NHWA PHARMA CORPORATION
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