Method for preparing octreotide acetate

A technology of octreotide acetate and octreotide, applied in the field of medicine, can solve the problems of long half-life, long reaction time, low production efficiency and the like

Active Publication Date: 2019-01-11
成都天台山制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] (2) Long half-life: the half-life of subcutaneous injection is 2 hours
However, the cyclization reactio

Method used

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  • Method for preparing octreotide acetate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the preparation of octreotide acetate

[0088] 1. Synthetic peptide chain

[0089] (1) Preparation of Boc-Thr(tBu)-OCs

[0090] Take 30.3 g of Boc-Thr(tBu)-OH (FW: 275.3, 110 mmol), dissolve it in 250 ml of methanol and 250 ml of water, pH 2.5. Take another 24g of cesium carbonate (147mmol) and add 100ml of water to dissolve until clear, and slowly add the above-mentioned Boc-Thr(tBu)-OH solution under stirring, and carbon dioxide gas will be generated. The pH of the solution was 7.5. It was dissolved in water at 40-50°C and concentrated to dryness under reduced pressure to obtain 54.2 g of Boc-Thr(tBu)-OCs as a syrupy residue.

[0091] (2) Preparation of Boc-Thr(tBu)-O-resin

[0092] Get 100 grams of chloromethyl resin (100-200 mesh, 1.0mmol / g, 100mmol), soak in DMF for 30 minutes, make the resin fully swell, add step (1) gained syrupy residue 107g and DMF of 700ml, 50- React at 55°C for 48 hours.

[0093] After filtering, the resin was washed twice...

Embodiment 2

[0124] Embodiment 2: the preparation of octreotide acetate

[0125] 1. Synthetic peptide chain

[0126] With embodiment 1.

[0127] Two, disulfide bond ring formation

[0128] Dissolve 90g of the reduced octreotide crude product in 90L of water, slowly add 2M ammonia water dropwise to pH7.8 under stirring, and feed air into the solution at room temperature (the used air passes through saturated calcium hydroxide solution and 2M sulfuric acid solution in advance successively) ), so that the disulfide bonds undergo ring-forming reaction for about 24-36 hours, add glacial acetic acid to adjust the pH to 5.5, add activated carbon to stir for 30 minutes, and filter.

[0129] 3. Separation and purification

[0130] Gained whole filtrate is purified in batches through C18 column when disulfide bonds are formed into rings, mobile phase: 0.25mol / L potassium acetate: acetonitrile (7.2:2.8); Flow rate is: 800ml / min; Effluent, the detection wavelength is: 280nm; After the sample pea...

Embodiment 3

[0131] Embodiment 3: the preparation of octreotide acetate

[0132] 1. Synthetic peptide chain

[0133] With embodiment 1.

[0134] Two, disulfide bond ring formation

[0135] Dissolve 90g of the reduced octreotide crude product in 90L of water, slowly add 2M ammonia water dropwise to pH7.8 under stirring, and feed air into the solution at room temperature (the used air passes through 2M sulfuric acid solution and saturated calcium hydroxide solution successively in advance) ), so that the disulfide bonds undergo ring-forming reaction for about 24-36 hours, add glacial acetic acid to adjust the pH to 5.5, add activated carbon to stir for 30 minutes, and filter.

[0136] 3. Separation and purification

[0137] Gained whole filtrate is purified in batches through C18 column when disulfide bonds are formed into rings, mobile phase: 0.25mol / L potassium acetate: acetonitrile (7.2:2.8); Flow rate is: 800ml / min; Effluent, the detection wavelength is: 280nm; After the sample pea...

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Abstract

The invention relates to a method for preparing octreotide acetate, in particular to a method for preparing the octreotide acetate. The method comprises the following steps of preparing a cesium saltfrom Boc-Thr(tBu)-OH by taking merrifield resin as an initial raw material, sequentially connecting amino acids with protection groups to obtain protection octapeptide resin according to a method of solid phase synthesis, sequentially stripping a Boc-protection group by employing HC1/isopropyl alcohol, and performing peptide grafting reaction by employing a condensing agent; reducing with palladium carbon/hydrogen, and simultaneously cutting a peptide chain to obtain reduced octreotide; allowing the reduced octreotide, an oxidizing agent and an additive to react to generate an octreotide roughproduct with looped disulfide bond; and performing separation and purification on the octreotide rough product with a C18 column to prepare an octreotide acetate refined product. The invention also relates to an octreotide acetate injection medium composition and a quality detection method thereof. The method shows an excellent technological effect; and compared with a traditional method, the method has the advantages of high production efficiency, high yield and a few impurities.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically, the invention discloses a preparation method of octreotide acetate, and the invention also discloses an injection pharmaceutical composition of octreotide acetate. The octreotide acetate and octreotide acetate injection pharmaceutical composition prepared by the present invention have excellent properties. For example, the method for preparing octreotide acetate of the present invention can make the content of oxidative degradation impurities in the product lower, and the preparation efficiency of the method is significantly better. Background technique [0002] Octreotide Acetate (Octreotide Acetate) is a synthetic polypeptide composed of eight amino acids, its chemical name is: D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophanyl-L- Lysyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl]-L-cysteineamide ring (2→7)-disulfide bond Acetate, its English chemical ...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06C07K7/06C07K1/16C07K1/06C07K1/04
CPCG01N30/02G01N30/06C07K7/06Y02P20/55
Inventor 王敬江威姚波张莲莲余茹吕吉赵东明
Owner 成都天台山制药股份有限公司
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