Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to Florfenicol

a technology of oxazolidine and aminodiol, which is applied in the field of process for preparing oxazolidine protected aminodiol compounds, can solve the problems of difficult isolation and handling, high cost of aminodiol compounds of formula iii, and increase yield , the effect of reducing cos

Inactive Publication Date: 2007-03-08
SCHERING PLOUGH ANIMAL HEALTH +2
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  • Abstract
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AI Technical Summary

Benefits of technology

[0039] The use of the esters of Formulas IV and VI generates the expensive free base starting material of Formula III in situ, thereby eliminating the need to isolate this difficult to isolate compound. Yield losses for the free base starting material of Formula III due to isolation are thus eliminated with resulting increased yield and lower cost for the oxazolidine protected aminodiol compound of Formula V, or specifically the compound of Formula II, or in the more preferred embodiment the oxazolidine protected aminodiol compound of Formula XII. Applicants have also found ways to utilize the compound of Formula IV with more efficient and cost-saving processes. The present invention thus has the advantage of being an efficient and economical process for preparing Florfenicol, its analogs and oxazolidine intermediates related thereto.

Problems solved by technology

A major drawback of the process disclosed in 2005 / 0075506 A1 is the use of the aminodiol starting material of Formula III.
The aminodiol compound of Formula III is expensive.
It is also difficult to isolate and handle due to its amphoteric nature.

Method used

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  • Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to Florfenicol
  • Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to Florfenicol
  • Process for preparing oxazolidine protected aminodiol compounds useful as intermediates to Florfenicol

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II)

[0130] (2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene (500 mL) and acetone (500 mL) replace methanol which distills off. Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at 75-85° C. for 12-18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of potassium carbonate (19.0 g, 0.1914 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the...

example 2

Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II)

[0131] (2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in methanol (450 mL) reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.4 g, 0.3480 moles) in solution. Toluene (450 mL) and acetone (450 mL) replace methanol which distills off. Addition of triethylamine (8.8 g, 0.0870 moles) with heating at 70-80° C. for 12-18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of triethylamine (44.5 g, 0.4402 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product...

example 3

Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II)

[0132] (2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in tetrahydrofuran (500 mL) reacts with lithium aluminum hydride (16.0 g, 0.4224 moles) over 4-8 hours at 60-70° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.36 g, 0.3480 moles). Addition of ethyl acetate (75 mL) destroys any excess lithium aluminum hydride. Addition of xylene (600 mL), 2-methoxypropene (37.6 g, 0.5220 moles), and p-toluenesulfonic acid monohydrate (6.6 g, 0.0348 moles) with agitation at 20-30° C. for 10-16 hours produces (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of triethylamine (81.3 g, 0.8039 moles) and acetyl chloride (30.0 g, 0.3828 moles...

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Abstract

An improved method of preparing oxazolidine protected aminodiol compounds is disclosed. These compounds are useful intermediates in processes for making Florfenicol.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a non-provisional application that claims priority under 35 U.S.C. § 119(e) of provisional application U.S. Ser. No. 60 / 714,685 filed Sep. 7, 2005, the contents of which are hereby incorporated by reference in their entireties.TECHNICAL FIELD [0002] The present invention relates generally to a new process for preparing oxazolidine protected aminodiol compounds. These compounds are useful intermediates in the process for making Florfenicol. BACKGROUND OF THE INVENTION [0003] Florfenicol is a broad spectrum antibiotic of Formula I [0004] It has wide spread application in veterinary medicine for the treatment of both Gram positive and Gram negative bacteria as well as rickettsial infections. Florfenicol is also known as [R—(R*,S*)]-2,2-Dichloro-N-[1-(fluoromethyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl]acetamide. [0005] Commonly-assigned U.S. Pat. No. 5,663,361, the disclosure of which is incorporated herein by re...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D263/02
CPCC07C315/04C07D263/04C07D263/06C07C317/32C07C317/48C07C315/00
Inventor TOWSON, JAMES C.
Owner SCHERING PLOUGH ANIMAL HEALTH
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