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Solid-phase synthesis process of angiotensinamide as well as intermediate and application thereof

A technology of blood-increasing hormone and condensation reaction, which can be used in medical preparations containing active ingredients, drug combinations, cardiovascular system diseases, etc., and can solve problems such as difficulty in complete dissociation

Active Publication Date: 2013-10-30
SPH NO 1 BIOCHEM & PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Therefore, the technical problem to be solved in the present invention is to overcome the existing vasopressin solid-phase synthesis method using chloromethyl resin, and finally need to use hydrobromic acid to dissociate the peptide chain from the resin, and the side chain protecting group nitro And benzyl is difficult to completely dissociate in the hydrogenation reaction, providing a new preparation method of vasopressin, which does not need to use hydrobromic acid to dissociate the peptide chain from the resin, and the side chain protecting group nitro dissociates completely from the benzyl group

Method used

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  • Solid-phase synthesis process of angiotensinamide as well as intermediate and application thereof
  • Solid-phase synthesis process of angiotensinamide as well as intermediate and application thereof
  • Solid-phase synthesis process of angiotensinamide as well as intermediate and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0116] 9. Preparation of vasopressin

[0117]

[0118] Adding protected vasopressin to peptide cutting reagent TFA:TIS:H 2 In O, react for 2-3 hours, filter with suction, concentrate the filtrate by distillation under reduced pressure, add ice-cold methyl tert-butyl ether to precipitate, and collect the crude vasopressin by centrifugation. The crude peptide was purified by reverse-phase high-performance liquid chromatography to obtain a pure white product.

Embodiment 1

[0120] Embodiment 1: the preparation of Fmoc-Phe-Wang resin

[0121] Weigh 50g of Wang resin (100-200, 1.23mmol / g), put it into a sand core reactor, wash it once with 500mL DMF, drain it, then use 500mL DCM to fully swell the resin, and drain it.

[0122] Add Fmoc-Phe-OH (MW: 387.4, 3 times the moles of Wang resin) 71.5g, HOBt (MW: 135.13, 3 times the moles of Wang resin) 24.9g, DIC (MW: 126.2, 3 times the moles of Wang resin) 3 times) 28.9mL, 300mL DMF, 100mL DCM, use the nitrogen flow to fully and uniformly contact with the peptide resin, and use the volatilization and endothermic of DCM to quickly cool down the entire reaction system to 16 ° C, slowly add DMAP (MW: 122, Wang resin mole 0.2 times the number) 1.5 g, and the mixture was stirred at 26°C for 18 hours. Vacuum-dried, washed twice with DMF, and vacuum-dried. Add Pyridine (MW: 79.1, 10 times the number of moles of Wang resin) 49mL, Ac 2 O (MW: 102.09, 10 times the number of moles of Wang resin) 58mL, 500mL DCM, t...

Embodiment 2

[0123] Embodiment 2: the preparation of Fmoc-Pro-Phe-Wang resin

[0124] Add 500mL 20% Pi p / DMF solution, stir at 25°C for 10 minutes, vacuum dry, then add 500mL 20% Pi p / DMF solution, stir at 25°C for 20 minutes, vacuum dry, wash once with DMF, MeOH Twice, washed once with DMF, once with DCM, and dried in vacuo. Add 40.5g of Fmoc-Pro-OH (MW: 337.4, twice the molar number of Fmoc-Phe-Wang resin), 16.2g of HOBt (MW: 135.13, twice the molar number of Fmoc-Phe-Wang resin), HBTU (MW : 379.25, 2 times the number of moles of Fmoc-Phe-Wang resin) 45.5g, 350mL DMF, 100mL DCM, use the nitrogen flow to fully and evenly contact the peptide resin, and use the volatilization and heat absorption of DCM to quickly cool the entire reaction system to 15 °C , DIPEA (MW: 129.24, 2 times the mole number of Fmoc-Phe-Wang resin) 31.4mL was added dropwise, and the mixture was stirred at 25°C for 2.5 hours. Chlorobenzoquinone was tested negative, dried in vacuo, washed once with MeOH, DMF Wash twic...

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Abstract

The invention discloses a process for producing angiotensinamide with a chemical structure of H-Asn-Arg-Val-Tyr-Val-His-Pro-Phe-OH by adopting solid-phase synthesis technology and an intermediate adopted in the method. The method comprises the following steps of: (a) preparing protected angiotensinamide with a chemical structure of R1-Asn-Arg(R2)-Val-Tyr(R3)-Val-His(R4)-Pro-Phe-R5, wherein R1 is an amino protecting group, R2, R3 and R4 are side chain protecting groups, and R5 is carboxyl resin; and (b) under the action of a cutting reagent, deprotecting and separating the protected angiotensinamide obtained in the step (a) from the resin to generate angiotensinamide with the chemical structure of H-Asn-Arg-Val-Tyr-Val-His-Pro-Phe-OH. The method for synthesizing angiotensinamide is environment-friendly and efficient, has low requirements for equipment, and can be applied to large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis technology. More specifically, the present invention relates to a solid-phase synthesis process of vasopressin, its intermediates and applications. Background technique [0002] Hypertensin is a blood pressure-increasing drug, CAS registration number 53-73-6, English name angiotensinamide or [Asn 1 , Val 5 ]-angiotensin II, the chemical structure is H-Asn-Arg-Val-Tyr-Val-His-Pro-Phe-OH (2003 National Drug Standard WS-10001-(HD-1448)-2003). Vasopressin is used for hypotension caused by trauma or postoperative shock and general anesthesia or lumbar anesthesia, etc., can prevent or treat perioperative hypotension, and can be used as emergency medicine to treat shock hypotension, and can also be used to treat vascular tension In case of overdose of the conversion enzyme inhibitor and conventional treatment is ineffective. [0003] When cardiovascular homeostasis is threatened, neurohormonal...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P9/00
CPCY02P20/55
Inventor 黄臻辉丁金国江锡铭洪勇霍建丽琚姝
Owner SPH NO 1 BIOCHEM & PHARMA CO LTD
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