Preparation method of 4-hydroxy ciclosporin

A technology of hydroxycyclosporine and cyclosporine, which is applied in the field of organic synthesis and can solve problems such as difficult industrial production, low yield, and difficult purification

Active Publication Date: 2017-10-03
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The existing 4-hydroxycyclosporin preparation method has low yield, requires multi-step column chromatography, is difficult to purify, and is difficult to carry out industrial production

Method used

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  • Preparation method of 4-hydroxy ciclosporin

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preparation example Construction

[0049] Concrete, the preparation method of 4-hydroxycyclosporin comprises the following steps:

[0050] Step 1. Dissolve compound 2 and the first reactant in the first organic solvent at -20°C to 35°C (preferably in ice bath), and then add 3- Chloro-2-methylpropene, then heated to 58°C-62°C (preferably 60°C) and fully reacted (reaction time is preferably 2h), then added water and adjusted the pH to 7 with an acidic regulator, purified after sufficient reaction to obtain Compound 3.

[0051] The first reactant is selected from NaH, KH, K 2 CO and Cs 2 CO 3 at least one of the .

[0052] The acid regulator is hydrochloric acid, citric acid, sulfuric acid or fluoboric acid. Preferably, the acid regulator is hydrochloric acid (with a concentration of 0.5 mol / L-12 mol / L).

[0053] The structural formulas of compound 2, 3-chloro-2-methylpropene and compound 3 are as follows,

[0054] Compound 2: Compound 3:

[0055] In step 1, NaH and 3-chloro-2-methylpropene were added ...

Embodiment 1

[0137] Step 1. Compound 2 (diethyl acetylaminomalonate, 217.1 g, 1.0 mol) was dissolved in 2.0 L of DMF, and then NaH (60 wt% dissolved in kerosene, 48.0 g, 1.2 mol) was added. 3-Chloro-2-methylpropene (108.7 g, 117.5 mL, 1.2 mol) was then added under ice cooling, and the addition was completed within 30 min. The temperature was then heated to 60°C and maintained for 2 hours. Water (2.0 L) was then added, and the pH of the solution was adjusted to 7 with 1.0 mol / L HCl. At room temperature, reacted for 12 h, the precipitated white solid was collected by filtration, washed with distilled water (2×1 L), and finally dried in a vacuum oven to obtain compound 3 (247.0 g, 91%).

[0138] Step 2. Dissolve compound 3 (108.6 g, 0.5 mol) in 0.5 L of ethanol, add 0.5 L of 3.0 M NaOH aqueous solution, react under reflux for 3 h, then remove ethanol, and then adjust the pH with concentrated hydrochloric acid (12 mol / L) The value was 7, refluxed for 2h, and then the pH value of the solution...

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Abstract

The invention relates to a preparation method of 4-hydroxy ciclosporin. 4-hydroxy ciclosporin is prepared from cyclosporine A as a main raw material through chemical synthesis. In preparation of 4-hydroxy ciclosporin, the preparation method has a fast chemical synthesis rate, realizes a low cost and is easy to operate. The 4-hydroxy ciclosporin has high purity. The preparation method realizes large-scale preparation of 4-hydroxy ciclosporin.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of 4-hydroxycyclosporine. Background technique [0002] 4-hydroxycyclosporine ((γ-hydroxylmethylleucine 4 )-cyclosporin A) was first developed by Sandoz (SANDOZ) Pharmaceutical Company in 1991 as an AIDS-inhibiting activity of cyclosporin immunosuppressive derivatives. 4-Hydroxycyclosporine is obtained by oxidation of the γ-position of the leucine side chain at the 4-position of cyclosporine, and the structural formula is (Compound 1). [0003] 4-Hydroxycyclosporine is widely used as an intermediate in the research and development of antiviral molecules. For example, the anti-HCV clinical drug molecule SCY-635 developed by Scynexis is exactly in (γ-hydroxylmethylleucine 4 )-cyclosporin A and then obtained through 3-position modification. In addition, (γ-hydroxylmethylleucine 4 )-cyclosporin A itself also has a good hair growth effect. [0004] The exi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/02
CPCC07K7/645
Inventor 张庆舟张伟滨林光龚建贤杨震
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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