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Somatostatin full-synthesis method

A somatostatin, total synthesis technology, applied in the biological field, can solve the problems of many reaction steps, lengthy routes, and difficulty in solvent distillation.

Inactive Publication Date: 2007-09-19
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this liquid-phase method exists: (1) reaction step is many, and route is tedious
(2) The intermediate is not easy to purify and separate, and it is difficult to evaporate the solvent in actual operation
(3) The source and preparation of the reagent and the amino acid side chain protecting group used are relatively difficult, which reduces the cost advantage and is difficult to be suitable for mass production
The method also needs to adopt conditions such as hydrogen fluoride, without changing the deficiencies in the above-mentioned solid-phase method and liquid-phase method.

Method used

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  • Somatostatin full-synthesis method
  • Somatostatin full-synthesis method
  • Somatostatin full-synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]N α -9-fluorenylmethoxycarbonyl-O-tert-butyl-seryl-N min - Preparation of trityl-cysteinyl-2-chloro-trityl resin

[0050]

[0051]

[0052] Reagent

Feeding amount

moles

N α -9-fluorenylmethoxycarbonyl

-O-tert-butyl-serine

Fmoc-Ser(tBu)-OH

1.54g

4mmol

Fmoc-Cys(Trt)-(R)

4g

2mmol

HOB

0.54g

4mmol

DCC / DCM solution

4ml

4mmol

20% piperidine / DMF solution

50ml×2

DCM

about 320ml

MeOH

about 300ml

DMF

Appropriate amount

[0053] Operation: (1) Put the Fmoc-Cys(Trt)-(R) resin in a peptide synthesizer, alternately wash twice with DCM and MeOH each 30ml×2, 2min / time, drain, add 20% piperidine / DMF solution 50ml×2 room temperature. Stir for 20 min, 2 times (to remove Fmoc), drain, and wash the resin alternately with DCM and MeOH each 30ml×3 for 3 times, 2 min each time, and drain. Kasier reagent test, the resul...

Embodiment 2

[0060] N α -9-fluorenylmethoxycarbonyl-O-tert-butyl-threonyl-O-tert-butyl-seryl-N im - Preparation of trityl-cysteinyl-2-chloro-trityl resin

[0061] Reaction formula:

[0062]

[0063]

[0064] Reagent

Feeding amount

moles

resin

2mmol

Fmoc-Thr(tBu)

-OH

1.6g

4mmol

HOB

0.54g

4mmol

DCC / DCM solution

4ml

4mmol

20% piperidine / DMF solution

liquid

100ml

DCM

about 320ml

MeOH

about 300ml

DMF

Appropriate amount

[0065] Operation: (1) Add 20% piperidine / DMF solution 50ml×2 to the resin, stir at room temperature for 20min, twice (to remove Fmoc), drain, and wash the resin alternately with 30ml×3 DCM and MeOH for 3 times, 2min / Once, drain the Kaiser reagent. Test, the result is positive, Fmoc has been removed, if it is negative, continue to go to Fmoc until it is positive.

[0066] (2) Add the DCM / DMF solution containi...

Embodiment 3

[0072] N α -9-fluorenylmethoxycarbonyl-phenylalanyl-O-tert-butyl-threonyl-O-tert-butyl-seryl-N im - Preparation of trityl-cysteinyl-2-chloro-trityl resin

[0073] Reaction formula:

[0074]

[0075]

[0076]

[0077] Reagent

Feeding amount

moles

resin

2mmol

Fmoc-Phe-OH

1.55g

4mmol

HOB

0.54g

4mmol

DCC / DCM solution

4ml

4mmol

20% piperidine / DMF solution

100ml

DCM

about 320ml

MeOH

about 300ml

DMF

Appropriate amount

[0078] Operation: (1) Add 20% piperidine / DMF solution 50ml×2 to the resin, stir at room temperature for 20min, twice (to remove Fmoc), drain, and wash the resin alternately with 30ml×3 DCM and MeOH for 3 times, 2min / Once, drain the Kaiser reagent. Test: The result was positive, Fmoc has gone.

[0079] (2) Add the DCM / DMF solution containing Fmoc-Phe-OH and HOBt to the resin, add 4ml of DCC / DCM solution, and stir a...

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Abstract

The present invention discloses a solid synthesis method of somatostatic (14 peptide). Said method adopts 2-chlorotrityl resin as solid carrier and includes the following steps: firstly, connecting said resin with protective cysteinyl (Fmoc-Cys(Trt)-), adopting programmed peptide-connecting method Fmoc protecting amino acid to implement synthesis of somatostatic linear peptide, using trifluoacetic acid to remove linear peptide side-chain protection group by means of one step process and cutting resin so as to obtain the trifluoacetic acid of somatostatin linear peptide, making said intermediate product undergo the process of oxidative ring-closing reaction in aqueous hydrogen peroxide solution or dimethyl sulphoxide aqueous solution to obtain the somatostatin trifluoacetic acid salt crude product, then making the crude product pass through C18 bonded silica-gel medium pressure column, and adopting methyl alcohol-water elution process to make separation and purification so as to obtain its refined product.

Description

technical field [0001] The invention belongs to the field of biotechnology. It specifically relates to a total synthesis method of somatostatin. Background technique [0002] Somatostatin (somatostatin) chemical name: alanyl-glycyl-cysteinyl-lysyl-asparaginyl-phenylalanyl-phenylalanyl-tryptophanyl-lysyl-threonyl Aminoacyl-phenylalanyl-threonyl-seryl-cysteine ​​(3,14) disulfide ring (Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe -Thr-Ser-Cysteine ​​Cydic(3→14)disulphide [0003] The chemical structural formula is: [0004] [0005] Molecular formula: C 76 h 104 N 18 o 19 S 2 [0006] Molecular weight: 1638 [0007] This product is a synthetic 14-peptide cyclic compound. The chemical structure is exactly the same as that of natural somatostatin (growth hormone release inhibitory hormone). The reports of artificial synthesis of this product include chemical synthesis and biosynthesis, among which chemical synthesis includes liquid phase peptide synthesis and solid ...

Claims

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Application Information

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IPC IPC(8): C07K7/64
Inventor 严益民屠永锐孙永强马亚平邓金根
Owner CHANGZHOU NO 4 PHARMA FACTORY
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