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A kind of method for carboxyl protection preparation oritavancin

A carboxyl-protecting group and carboxyl-based technology, applied in peptide preparation methods, chemical instruments and methods, bulk chemical production, etc., can solve the problems that BrettpHos ligands are expensive and unsuitable for industrialization

Active Publication Date: 2021-04-13
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] CN106188243 A discloses the synthetic steps of oritavancin, in catalyst [2-(dicyclohexylphosphorus)-3,6-methoxy-2',4',6'-triisopropyl-1,1' - Biphenyl][2-(2-aminoethyl)benzene]palladium chloride, ligand 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri In the presence of isopropyl-11'-biphenyl, base and solvent, react with compound side chain 4'-chlorobiphenyl-4-carbaldehyde to obtain oritavancin with a yield of 65%, but the BrettpHos catalyst , BrettpHos ligands are expensive and not suitable for industrialization

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  • A kind of method for carboxyl protection preparation oritavancin
  • A kind of method for carboxyl protection preparation oritavancin
  • A kind of method for carboxyl protection preparation oritavancin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Synthesis of Esterification Intermediate 3:

[0056]

[0057] 1) 200mg starting material A82846B dissolved in 15mL CH 3 In OH solvent, add 0.02mL concentrated sulfuric acid dropwise, and react at 60°C for 3h;

[0058] 2) Add 50 mL of ether, filter with suction, and wash the solid with ether. Obtain 192mg powder, yield 95%;

[0059] Synthesis of oritavancin:

[0060]

[0061] 3) 150 mg of intermediate compound 3 was dissolved in 15 mL of a mixed solvent of DMSO / DMF / MeOH (1:1:1, V / V / V), and 26 mg of 4'-chlorobiphenyl-4-carbaldehyde was added, 20-50 Stir at ℃ for 2h, slowly add 12mg NaBH in batches 3 CN, react at 25-30°C for 5 h;

[0062] 4) Add 100 mL of acetone, filter with suction, wash the solid with acetone, and dry to obtain 147 mg of brown powder of intermediate compound 4;

[0063] 5) Add intermediate 5 to 15 mL CH containing 10 mg NaOH 3 OH / H 2 In a mixed solvent of O (1:1, V / V), react at 60°C for 2h;

[0064] 6) Add glacial acetic acid dropwise to ...

Embodiment 2

[0066] Synthesis of esterified intermediate 5:

[0067]

[0068] 1) Dissolve 200 mg of starting material A82846B and 23 mg of p-nitrophenol in 15 mL of DMSO solvent, add 0.02 mL of concentrated sulfuric acid dropwise, and react at 100 °C for 1 h;

[0069] 2) Add 50 mL of diethyl ether, filter with suction, and wash the solid with diethyl ether; 211 mg of powder is obtained, with a yield of 97%;

[0070] Synthesis of oritavancin:

[0071]

[0072] 3) 200 mg of intermediate compound 5 was dissolved in 20 mL of a mixed solvent of DMSO / DMF / MeOH (1:1:1, V / V / V), and 38 mg of 4'-chlorobiphenyl-4-carbaldehyde was added, 20-50 Stir at ℃ for 2h, slowly add 15mg NaBH in batches 3 CN, react at 25-30°C for 4 h;

[0073] 4) Add 150mL of acetone, filter with suction, wash the solid with acetone; dry to obtain 189mg of brown powder of intermediate compound 6;

[0074] 5) Add intermediate 5 to 20 mL CH containing 20 mg NaOH 3 OH / H 2 In a mixed solvent of O (1:1, V / V), react at 60°C...

Embodiment 3

[0077] Synthesis of esterified intermediate 7:

[0078]

[0079] 1) Dissolve 150mg of starting material A82846B in 15mL (CH 3 ) 2 In CHOH solvent, add 0.02mL concentrated sulfuric acid dropwise, and react at 75-80°C for 2h;

[0080] 2) Add 50 mL of diethyl ether, filter with suction, and wash the solid with diethyl ether; 149 mg of powder is obtained, with a yield of 97%;

[0081] Synthesis of oritavancin:

[0082]

[0083] 3) 120mg of intermediate compound 7 was dissolved in 15mL DMSO / DMF / (CH 3 ) 2 In the mixed solvent of CHOH (1:1:1, V / V / V), add 24 mg 4'-chlorobiphenyl-4-carbaldehyde, stir at 20-50°C for 2 hours, slowly add 10 mg NaBH in batches 3 CN, react at 25-30°C for 4 h;

[0084] 4) Add 100 mL of acetone, filter with suction, and wash the solid with acetone; dry to obtain 118 mg of brown powder of intermediate compound 8;

[0085] 5) Add intermediate 5 to 15 mL CH containing 10 mg NaOH 3 OH / H 2 In a mixed solvent of O (1:1, V / V), react at 60°C for 2h;

...

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Abstract

The invention discloses a method for preparing oritavancin by carboxyl protection, which comprises: protecting the carboxyl group of A82846B, then performing aldehyde-amine condensation with 4'-chlorobiphenyl-4-formaldehyde, then reducing the C=N bond, and finally The carboxyl protecting group is removed to obtain oritavancin. The present invention breaks through the limitations of the prior art. In the synthesis process of oritavancin, the operation of protecting the carboxyl group of A82846B is added, and the subsequent synthesis such as aldehyde-amine condensation with 4'-chlorobiphenyl-4-formaldehyde is added. operation, unexpectedly improved the selectivity of the reaction, not only did not reduce the final yield of oritavancin, but effectively improved the efficiency of subsequent reactions, reduced the generation of by-products, and improved the yield and purity of oritavancin. have unexpected effects.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a synthesis process of a pharmaceutical intermediate, in particular to a method for preparing oritavancin. Background technique [0002] Oritavancin DipHospHate (CAS: 192564-14-0), trade name Orbactiv / Nuvocid, has a specific three-dimensional structure, and its structural formula is as follows: [0003] [0004] On August 7, 2014, the FDA approved the antibiotic Orbactiv (oritavancin, oritavancin, IV) injection for acute bacterial infection caused by sensitive Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, MRSA). Treatment of adult patients with skin and skin structure infections (ABSSSIs). Orbactiv is the first and only single-dose antibiotic approved by the FDA for the treatment of ABSSSIs. Patients received just one Orbactiv infusion and the entire treatment regimen was over. The approval of Orbactiv also represents a major advance in the treatment...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K9/00C07K1/06
CPCC07K9/008Y02P20/55
Inventor 李冰冰姜桥王龙书卢增杰
Owner LIVZON NEW NORTH RIVER PHARMA
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