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Method for preparing oritavancin by means of carboxyl protecting

A technology of carboxyl protecting group and carboxyl group, which is applied in peptide preparation methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of unsuitability for industrialization and expensive price of BrettpHos ligands, so as to improve yield and purity and reduce side effects Product production, selectivity enhancement effect

Active Publication Date: 2018-12-21
LIVZON NEW NORTH RIVER PHARMA
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  • Claims
  • Application Information

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Problems solved by technology

[0012] 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 ligand is expensive and not suitable for industrialization

Method used

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  • Method for preparing oritavancin by means of carboxyl protecting
  • Method for preparing oritavancin by means of carboxyl protecting
  • Method for preparing oritavancin by means of carboxyl protecting

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Synthesis of Esterification Intermediate 3:

[0057]

[0058] 1) 200 mg of starting material A82846B was dissolved in 15 mL of CH 3 In OH solvent, add 0.02mL concentrated sulfuric acid dropwise, and react at 60°C for 3h;

[0059] 2) Add 50 mL of ether, filter with suction, and wash the solid with ether. Obtained 192mg powder, yield 95%;

[0060] Synthesis of oritavancin:

[0061]

[0062] 3) Dissolve 150mg of intermediate compound 3 in 15mL of DMSO / DMF / MeOH (1:1:1, V / V / V) mixed solvent, add 26mg of 4'-chlorobiphenyl-4-carbaldehyde, 20~50℃ Under stirring for 2h, slowly add 12mg NaBH in batches 3 CN, react at 25~30℃ for 5h;

[0063] 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;

[0064] 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;

[0065] 6) Add glacial acetic acid dropwise to adjus...

Embodiment 2

[0067] Synthesis of esterified intermediate 5:

[0068]

[0069] 1) Dissolve 200mg of starting material A82846B and 23mg of p-nitrophenol in 15mL of DMSO solvent, add 0.02mL of concentrated sulfuric acid dropwise, and react at 100°C for 1h;

[0070] 2) Add 50 mL of diethyl ether, filter with suction, and wash the solid with diethyl ether; obtain 211 mg of powder with a yield of 97%;

[0071] Synthesis of oritavancin:

[0072]

[0073] 3) Dissolve 200mg of intermediate compound 5 in 20mL of DMSO / DMF / MeOH (1:1:1, V / V / V) mixed solvent, add 38mg of 4'-chlorobiphenyl-4-carbaldehyde, 20~50℃ Under stirring for 2h, slowly add 15mg NaBH in batches 3 CN, react at 25~30℃ for 4h;

[0074] 4) Add 150 mL of acetone, filter with suction, and wash the solid with acetone; dry to obtain 189 mg of brown powder of intermediate compound 6;

[0075] 5) Intermediate 5 was added 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 for 2h.

[0076] 6...

Embodiment 3

[0078] Synthesis of esterified intermediate 7:

[0079]

[0080] 1) 150 mg of starting material A82846B was dissolved in 15 mL (CH 3 ) 2 In CHOH solvent, add 0.02mL concentrated sulfuric acid dropwise, and react at 75-80°C for 2h;

[0081] 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%;

[0082] Synthesis of oritavancin:

[0083]

[0084] 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 24mg 4'-chlorobiphenyl-4-carbaldehyde, stir at 20~50℃ for 2h, slowly add 10mg NaBH in batches 3 CN, react at 25~30℃ for 4h;

[0085] 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;

[0086] 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;

[0...

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Abstract

The invention discloses a method for preparing oritavancin by means of carboxyl protecting. The method comprises the steps that carboxyl of A82846B is protected, then the A82846B and 4'-chlorobiphenyl-4-carbaldehyde are subjected to aldehyde-amine condensation, then a C=N bond is reduced, and finally, a carboxyl protecting group is removed to obtain the oritavancin. By means of the method for preparing the oritavancin by means of carboxyl protecting, limitation of the prior art is broken through, in an oritavancin synthesis process, operation of protecting the carboxyl of the A82846B and subsequent synthesis operation of conducting aldehyde-amine condensation on the A82846B and the 4'-chlorobiphenyl-4-carbaldehyde and the like are added, accidentally, the reaction selectivity is improved,not only is the final yield of the oritavancin not reduced, but also the efficiency of subsequent reaction is effectively improved, by-products are reduced, and the yield and the purity of the oritavancin are improved, so that the method has the 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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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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