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Preparation method of melanotan-II

A technology of notan and amino resin, which is applied in the field of preparing menanotan, can solve the problems of unfavorable industrial production, complicated operation, and low application value, and achieve the effects of increasing yield, simple operation, and reducing production cost

Inactive Publication Date: 2014-07-23
NANJING TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, there is no report about the synthetic process of Menanotan in China; foreign reports about the synthetic process of Menanotan, such as PNAS77 (10): 5754-5758, adopt Boc solid-phase synthesis process, complicated operation, and the yield is only 25%, a large amount of highly corrosive trifluoroacetic acid and hydrofluoric acid are used in the synthesis process, which is not conducive to industrial production and has low application value

Method used

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  • Preparation method of melanotan-II

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Such as figure 1 As shown, the preparation method claimed in the present invention comprises the following steps:

[0048] Step 1, Fmoc-L-Val-Rink Amide resin preparation

[0049] 1. Put 10 g of Rink Amide resin with a substitution degree of 0.6 mmol / g in the reactor, add NMP to wash twice, and then use NMP to swell for 1 hour.

[0050] 2. Add the piperidine NMP solution with a volume ratio of 1:4 to the swollen Rink Amide resin to remove the Fmoc protecting group on the Rink Amide resin. After the removal, wash with NMP 4 times, DCM 2 times, and methanol 2 times. Second-rate.

[0051] 3. Weigh 6.11g Fmoc-L-Val-OH, 2.43g HOBt, 6.83g HBTU, add 54ml NMP to dissolve, add 6.27ml DIPEA after completely dissolved, mix well and add to the reactor to start the reaction.

[0052] 4. React for 6 hours, finish the reaction, wash with NMP three times, measure 7.6ml of acetic anhydride and 6.5ml of pyridine, mix them in 40ml of NMP, add them to the reactor for 2 hours, wash with ...

Embodiment 2

[0070] Such as figure 1 As shown, the preparation method claimed in the present invention comprises the following steps:

[0071] Step 1, Fmoc-L-Val-Rink Amide resin preparation

[0072] 1. Put 30 g of Rink Amide resin with a substitution degree of 0.1 mmol / g in the reactor, add NMP to wash twice, and then use NMP to swell for 1 hour.

[0073] 2. Add the piperidine NMP solution with a volume ratio of 1:4 to the swollen Rink Amide resin to remove the Fmoc protecting group on the Rink Amide resin. After the removal, wash with NMP 4 times, DCM 2 times, and methanol 2 times. Second-rate.

[0074] 3. Weigh 10.2g Fmoc-L-Val-OH, 4.05g HOBt, 11.4g HBTU, add 80ml NMP to dissolve, add 10.5ml DIPEA after completely dissolved, mix well and add to the reactor to start the reaction.

[0075] 4. React for 1 hour, finish the reaction, wash with NMP three times, measure 3.8ml of acetic anhydride and 3.3ml of pyridine, mix them in 70ml of NMP, put them into the reactor for 2 hours, wash with...

Embodiment 3

[0093] Such as figure 1 As shown, the preparation method claimed in the present invention comprises the following steps:

[0094] Step 1, Fmoc-L-Val-Rink Amide resin preparation

[0095]1. Put 5 g of Rink Amide resin with a substitution degree of 1.6 mmol / g in the reactor, add NMP to wash twice, and then use NMP to swell for 1 hour.

[0096] 2. Add the piperidine NMP solution with a volume ratio of 1:4 to the swollen Rink Amide resin to remove the Fmoc protecting group on the Rink Amide resin. After the removal, wash with NMP 4 times, DCM 2 times, and methanol 2 times. Second-rate.

[0097] 3. Weigh 4.07g Fmoc-L-Val-OH, 1.62g HOBt, 4.55g HBTU, add 36ml NMP to dissolve, add 4.18ml DIPEA after completely dissolved, mix well and add to the reactor to start the reaction.

[0098] 4. React for 20 hours, finish the reaction, wash with NMP three times, measure 7.6ml of acetic anhydride and 6.5ml of pyridine, mix them in 40ml of NMP, add them to the reactor for 2 hours, wash with N...

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Abstract

The invention discloses a preparation method of melanotan-II, and the method comprises the following steps of: 1) obtaining Fmoc-L-Val-amino resin according to Fmoc-L-Val-OH and amino resin; 2) coupling the Fmoc-L-Val-amino resin to side chain protection group-containing melanotan-II-amino resin of which the N end is a free amino group one by one by a solid phase synthesis method according to the peptide sequence of the melanotan-II; 3) having a acetylation reaction to generate the side chain protection group-containing melanotan-II-amino resin; and 4) carrying out pyrolysis on the side chain protection group-containing melanotan-II-amino resin by a pyrolysis reagent, and precipitating the ice ether to obtain coarse peptide; and purifying and dryly freezing the coarse peptide to obtain the melanotan-II. The preparation technology method of the melanotan-II provided by the invention is wide in application prospect and considerable in economic and practical value.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a method for preparing Afamelanotide. Background technique [0002] Research confirms that skin tanning or skin pigmentation can protect people with photosensitive skin diseases from the sun and ultraviolet rays. Melanocortin peptide hormone alpha-melanocyte stimulating hormone (α-MSH) can make skin melanocytes produce melanin, and plays an important role in the process of light-induced tanning reaction. [0003] In 1995, US Patent No. 4,457,864 disclosed a series of -MSH analogues including Menanotan. The molecular structural formula of Menanotan is: acetyl-L-seryl-L-tyrosyl-L-seryl-L-norleucyl-L-glutamyl-L-histidyl-D- Phenylalanyl-L-Arginyl-L-Tryptophanyl-Glycyl-L-Lysyl-L-Prolyl-Valinamide. Menanotan is a synthetic -MSH analog originally developed by Arizona University, which has been proven to activate skin pigmentation, promote skin darkening, and relieve vari...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C07K1/06C07K1/04
CPCY02P20/55
Inventor 朱颐申周云隆韦萍欧阳平凯
Owner NANJING TECH UNIV
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