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A kind of method for preparing oritavancin

An intermediate and amine-based technology, which is applied in the synthesis process of pharmaceutical intermediates and the field of preparation of oritavancin, can solve the problems that BrettpHos ligands are expensive and not suitable for industrialization, so as to reduce the generation of by-products and increase the yield and purity, the effect of improving efficiency

Active Publication Date: 2021-08-24
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] CN106188243A discloses the synthesis steps of oritavancin, in the 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'-triiso In the presence of propyl-11'-biphenyl, alkali and solvent, react with compound side chain 4'-chlorobiphenyl-4-formaldehyde to obtain oritavancin with a yield of 65%, but the BrettpHos catalyst, BrettpHos ligands are expensive and unsuitable for industrialization

Method used

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  • A kind of method for preparing oritavancin
  • A kind of method for preparing oritavancin
  • A kind of method for preparing oritavancin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Synthesis of FMOC protecting group intermediate 3:

[0055]

[0056] 1) 330 mg of starting material A82846B was dissolved in 15 mL of H 2 In the mixed solvent of O / THF (1:1, V / V), add 0.1N NaOH dropwise to adjust pH=7, slowly add 10mL THF solution containing 101mg FmocOSu dropwise (add dropwise 0.1N NaOH to keep pH=7), 25~ React at 30°C for 6h;

[0057] 2) Add 50 mL of water to the reaction system, filter with suction, wash the solid with cold water at 4-10°C, dissolve the solid in 10 mL of DMSO, add 100 mL of acetone, filter with suction, wash the solid with acetone, and dry to obtain 327 mg, with a yield of 87%;

[0058] Synthesis of oritavancin:

[0059]

[0060] 3) Dissolve 300mg of intermediate compound 3 in 15mL of DMSO / DMF / MeOH (1:1:1, V / V / V) mixed solvent, add 54mg of 4'-chlorobiphenyl-4-carbaldehyde, 25-30°C Under stirring for 2h, slowly add 20mg NaBH in batches 3 CN, react at 25-30°C for 4h;

[0061] 4) Add 100 mL of acetone, filter with suction, an...

Embodiment 2

[0065] Synthesis of BOC protecting group intermediate 6:

[0066]

[0067] 1) 330 mg of starting material A82846B was dissolved in 15 mL of H 2 In the mixed solvent of O / dioxane (1:1, V / V), add 109mg Boc 2 O and 17 mg NaHCO 3 , react at 25-30°C for 6h;

[0068] 2) Add 50 mL of acetone to the reaction system, filter with suction, wash the solid with acetone, dissolve the solid in 10 mL of DMSO, add 100 mL of acetone, filter with suction, wash the solid with acetone, and dry to obtain 305 mg of intermediate compound 5 with a yield of 89%;

[0069] Synthesis of oritavancin:

[0070]

[0071] 3) Dissolve 300mg of intermediate compound 5 in 15mL of DMSO / DMF / MeOH (1:1:1, V / V / V) mixed solvent, add 54mg of 4'-chlorobiphenyl-4-carbaldehyde, 25-30°C Under stirring for 2h, slowly add 20mg NaBH in batches 3 CN, react at 25~30℃ for 4h;

[0072] 4) Add 100mL of acetone, filter with suction, and wash the solid with acetone; dry to obtain 307mg of brown powder of intermediate comp...

Embodiment 3

[0076] Synthesis of Cbz protecting group intermediate 7:

[0077]

[0078] 1) 330 mg of starting material A82846B was dissolved in 15 mL of H 2 In the mixed solvent of O / dioxane (1:1, V / V), add 103mg CbzOSu and 17mg NaHCO 3 , react at 25-30°C for 10h;

[0079] 2) Add 150 mL of acetone to the reaction system, filter with suction, wash the solid with acetone, dissolve the solid in 10 mL of DMSO, add 100 mL of acetone, filter with suction, wash the solid with acetone, and dry to obtain 311 mg of intermediate compound 7 with a yield of 87%;

[0080] Synthesis of oritavancin:

[0081]

[0082] 3) Dissolve 300mg of intermediate compound 7 in 15mL of DMSO / DMF / MeOH (1:1:1, V / V / V) mixed solvent, add 56mg of 4'-chlorobiphenyl-4-carbaldehyde, 25-30°C Under stirring for 2h, slowly add 21mg NaBH in batches 3 CN, react at 25~30℃ for 4h;

[0083] 4) Add 100 mL of acetone, filter with suction, wash the solid with acetone; dry to obtain 311 mg of brown powder of intermediate compoun...

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Abstract

The invention discloses a method for preparing oritavancin. The present invention breaks through the limitations of the prior art. In the synthesis process of oritavancin, the amine group at a specific site is first protected, and the synthesis operation steps are increased, and then subsequent synthesis operations are performed, which not only does not reduce the final product efficiency, while effectively improving the efficiency of subsequent reactions, reducing the generation of by-products, but improving the yield and purity of oritavancin.

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): C07K9/00C07K1/02C07K1/06
CPCC07K9/008Y02P20/55
Inventor 李冰冰姜桥王标陈月嫦谢伟健
Owner LIVZON NEW NORTH RIVER PHARMA
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