An Improved Process for Preparing Oxazolidine Protected Aminodiol Compounds Useful As Intermediates to Florfenicol
Technical Field
The present invention relates generally to a new process for preparing oxazoiidine protected aminodiol compounds. These compounds are useful intermediates in the process for making Florfenicol.
Background of the Invention
Florfenicol is a broad spectrum antibiotic of Formula I

preparing a compound of Formula II that is useful as an intermediate in the synthesis; of Florfenicol.


to generate a compound of Formula Xa;

wherein:
R1 is as defined above;

The term "halo" means fluoro, chloro, bromo or iodo. The term "halo aryl" means phenyl substituted by halo.

In one aspect of the invention, there is provided a process for preparing an oxazolidine protected aminodiol compound of Formula V:

wherein:
R1 is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl, C1.6 alkyl, C1.6 haloalkyl, C3.8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 alkoxy, C1-6 aralkyl. C2-6 aralkenyl, or C2-6 heterocyclic group;
R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1.6 alkoxy, C1-6 aralkyl, C2-6 aralkenyl, aryl, or C2-6 heterocyclic group;
R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-8 cycloalkyl, C2.a alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1.6 aralkyl, C2-6 aralkenyl, aryl or C2-6 heterocyclic group; and
R4 is hydrogen, OH, C1-6 alkyl, C1-6 haloalkyl, C3.8 cycloalkyl, benzyl, phenyl or C1.6 phenylalkyl group, where the phenyl ring may be substituted by one or two halogens, 1-6 alkyl or C1-6 alkoxy.
The compounds corresponding thereto are useful intermediates in the formation of Florfenicol and related compounds.
One preferred process corresponding to the invention includes the steps of:
a) reacting a compound of Formula VI:
wherein;
R1 is as defined above and R5 is hydrogen, C1-6 alkyl, C3.8 cycloalkyl, benzyl, phenyl or C1-6 alkylphenyl, in a vessel with a reducing agent in an alcoholic solvent to form an aminodiol compound of Formula VII:


wherein R1 is as defined above;
b) reacting the aminodiol compound of Formula VII in the vessel without
isolation (i.e., in situ) with an oxazolidine forming reagent to fonm a compound of
Fomnula VIII:

wherein R1, R2, R3 and R4 are as defined above; and
c) reacting the compound of Formula VIII in the vessel without isolation
(i, e., in situ) with a first N-acylating agent to form an oxazolidine protected aminodiol
compound of Formula V:

wherein R1, R2, R3 and R4 are as defined above.
Within the general process described above, there are certain currently preferred aspects of the invention:
R1 is methylthio, methylsulfoxy, or methylsulfonyl. More preferably, R1 is methylsulfonyl;

R2 and R3 are hydrogen, methyl, ethyl or propyl. More preferably, R2 and R3 are methyl;
R4 is a methyl, ethyl, propyl or isopropyl group. More preferably, R4 is methyl; and
R5 is methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl. The compound of Formula IV is commercially available. Alternative compounds corresponding to Formula VI can be prepared using standard organic synthetic techniques v^ithout undue experimentation.
One preferred ester compound corresponding to Formula VI is

wherein R5 is as defined above.
In a more preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula VI is the compound of Formula IV.
As mentioned above, the first part of the process calls for reacting a compound of Formula VI in a reaction vessel with a reducing agent. For purposes of the present invention, the term "reaction vessel" shall be understood to mean a container known to those of ordinary skill which is capable of holding the reactants

and allowing the reaction step to proceed to completion. The size and type of vessel will, of course, depend upon the size of the batch and the specific reactants selected.
A wide range of suitable reducing agents can be employed in carrying out the process of the invention, A non-limiting list of suitable reducing agents include NaBH4, KBH4, Ca(BH4)2, and LiBH4 and mixtures thereof when an alcoholic solvent is used. The alcoholic solvent can also be one of many art-recognized solvents but some preferred solvents include methanol, ethanol, propanol, isopropanol, butanol and pentanol and mixtures thereof. One preferred reducing agent is KBH4^
The molar ratio of reducing agent, such as KBH4, to the compound of Formula IV is between about 1:1 and about 2:1. Preferably, when the reducing agent is KBH4, the molar ratio of KBH4 to the compound of Fomiula IV is about 1.5:1 and the preferred solvent is methanol. This reduction can be carried out at a temperature of about sec to about 80°C in about 8 hours. Preferably, the temperature is below 60°C and the time for the reaction to reach completion is under 6 hours.
In an alternative aspect of the invention, the artisan can use reducing agents such as LiAIH4 or NaAlH4 When anhydrous conditions are desired. In such situations, solvents like ether or tetrahydrofuran can be used.
Once the aminodiol compound corresponding to Formula VII has been made, it is reacted, preferably in the same vessel (i.e., in situ), with an oxazolidine forming reagent such as formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixtures thereof, under conditions such as those set forth in the examples to make a compound of Formula VIII. One preferred aminodiol compound corresponding to Formula VII is

In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula VIII is the compound:


In a preferred embodiment, the methanol solvent is removed by distillation and replaced with another solvent designated herein as an oxazolidine forming solvent such as toluene, xylene, hexane or a mixture thereof. The preferred oxazolidine forming solvent is toluene. The ratio of the oxazolidine forming solvent to methanol is about 0.5:1 to 3:1 with the preferred ratio of about 1:1. An oxazolidine forming reagent such as formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixtures thereof is then added. One preferred oxazolidine forming reagent is acetone which is added in a ratio to toluene of about 0.5:1 to 3:1 with the preferred ratio of about 1:1. The reaction runs to completion to form the oxazolidine compound of Formula VIII over about 12 - 18 hours in the presence of a base designated herein as an oxazolidine promoting base such as potassium carbonate, sodium carbonate, trimethylamine or triethylamine. A preferred base is potassium carbonate or triethylamine. The oxazolidine forming reaction can be carried out at a temperature of about 65 - 85°C.
It is preferred that the compound of Formula VIII remain in the same vessel after completion of the reaction step when the first N-acylating agent is added. The nomenclature "first," "second" and "third" are used for describing the (1) N-acylating (first) agents so as to distinguish the agents used for making the oxazolidine protected aminodiol compounds of Formula V, from the (2) N-acylating agents (second) which are used in the formation of the compounds of Formula XI after the intermediate of Formula X has been formed, from the (3) N-acylating agents (third) used during the process to form the oxazolidine protected aminodiol compounds of Formula XII. Thus, some preferred first N-acylating compounds are of the formula R6COR4

wherein:
R4 is hydrogen, OH, C1-6alkyl, C1-6haloalkyl, C3-8 cycloalkyl, benzyl, phenyl or C1-6 phenylalkyl group, where the phenyl ring may be substituted by one or two halogens, C1-6alkyl or C1-6alkoxy; and
Re is halo, or C1-6 alkoxy.
Sonr^e more preferred first acylating agents include acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyl chloride, methyl chloroformate, ethyl chiorofonnate, propyl chloroformate and mixtures thereof.
In a pretended embodiment when Florfenicol is the desired end product, the compound corresponding to Formula V is the compound:

In a preferred embodiment, a base such as potassium carbonate, sodium carbonate, trimethylamine or triethylamine is added in a molar equivalent ratio to the compound of Formula VII of about 1:1 to 1:3, The preferred base is potassium carbonate or triethylamine and the preferred molar equivalent ratio is about 1.1 to 1. The preferred first N-acylating agent acetyl chloride is added in a hiolar ratio to the compound of Formula VII of about 1:1 to 3:1 with the preferred ratio being 1.1:1, Reaction temperature is about 20 - 30°C and the reaction completes in about 2 - 4 hours.
After the oxazolidine protected aminodiol compound of Formula V has been prepared, it can be used in the synthesis of Florfenicol and related compounds. Thus, in a further aspect of the invention, the inventive process continues by fluorinating the compound of Formula V:


wherein R1, R2, R3 and R4 are as defined above, with a fluorinating agent in the presence of an organic solvent to obtain a compound of Formula IX:

wherein R1, R2, R3 and R4 are as defined above.
In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula IX is specifically:

Suitable fluorinating agents include, without limitation, N-(2-chloro-1,1,2-trifluoroethyl)diethylamine, N-(2-chloro-1,1,2-trifluoro€thyl)dimethylamine, N-(2-chloro-1,1,2-trifluoroethyl)dipropylamine, N-(2-chloro-1,1,2-trifluoroethyl)pyrrolidine, N-(2-chloro-1,1,2-trifluoroethyl)-2-methylpyrrolidine, N-(2-chloro-1,1,2-trifluoroethyl)-4-methylpiperazine, N-(2-chloro-1,1,24rifluoroethyl}-morpholine, N-(2-chloro-1,1,2-trifluoroethyl)piperidine, 1,1,2,2-tetrafluoroethyUN,N-dimethylamine, (Diethylamino) sulfurtrifluoride, Bis-(2-methoxyethyl)aminosulfur thfluoride, N,N-diethyl-1.1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) and mixtures thereof. One preferred fluorinating agent is N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine.

The molar ratio of the fluorinating agent such as N.N.-diethyl-l,1,2,3,3,3-hexafluoro-1-propanamine to the compound according to Formula V is between about 1:1 and about 2:1, Preferably, the molar ratio of the N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine to the compound of Formula V is about 1.5:1. The fluorinating step can be carried out at a temperature of from about 80°C to about 110oC and at a pressure of about 60 psi.
The organic solvent used during the fluorinating step is preferably 1,2-dichloroethane, methylene chloride, chloroform, chlorobenzene, chlorinated hydrocarbons or mixtures thereof. A more preferred organic solvent is methylene chloride.
After the compound of Formula IX has been made, it is hydrolyzed with acid to form the compound of Formula X:

wherein R1 is as defined above, preferably, R1 is CH3SO2.
The acid used in this part of the process can be an inorganic acid like aqueous hydrochloric acid, sulfuric acid, or phosphoric acid or an organic acid like methanesulfonic acid. The hydrolyzing step is preferably carried out by heating the compound of Formula IX with 6N aqueous hydrochloric acid at a temperature of from about 90°C to about 105°C for about 60 minutes. Other suitable hydrolyzing steps will be apparent to those of ordinary skill.
In one preferred aspect of this embodiment when Fiorfenicol is the desired end product, the compound corresponding to Formula X is:


After hydrolysis has been completed, the compound of Formula X is reacted without isolation (i.e., in situ) with a second N-acylating agent to make compounds of Formula XI:

wherein R1 is the same as above, preferably CH3SO2; and R7 is hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6 dihaloalkyl, C1-6 trihaloalkyl, C3-8 cycloalkyl, C2-8 cyclohaloalkyl, C3-8 cyclodihaloalkyl, C3-8 cyclotrihaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 aralkyl, C2-6 aralkenyl, C2-6 heterocyclic benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, C1-6 alkyl or C1-6alkoxy. Preferably, R7 is CH2CI, CHCI2, CCI3. CH2Br, CHBr2, CBr3, CH2F, CHF2, or CF3, Thus, one preferred compound of Formula XI is:

wherein Ryis as defined above.
In one prefen^ed aspect of this embodiment when Florfenicol is the desired end product the compound corresponding to Formula XI is the compound of Formula I:


Suitable second N-acylating compounds are of the formula R6COR7, wherein R7 is the same as that described above and R6 is OH, halo or C1-6alkoxy. Some more preferred second N-acylating agents include dichloroacetic acid or a reactive derivative thereof. A non-limiting list includes reagents such as methyldichloroacetate, ethyidichloroacetate, or dichloroacetylchioride.
The second N-acylation step is preferably canried out by reacting the compound of Formula X in methanol with methyldichloroacetate at a temperature of from about 20°C to about 30°C for about 12 hours.
After the compound of Formula XI is made and rf necessary, the compound of Fonnula XI can optionally be purified by heating in a mixture of an alkyl mono, di or tri alcohols and water. The alcohols in this part of the process can be C1.10 monoalcohols, C1-10dialcohols and C1-10trialcohols and mixtures thereof. A non-limiting list of the C1-10 monoalcohols includes methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol and pentanol. One preferred G1-10 monoalcohol is isopropanol. A non-limiting list of the C1-10dialcohols Includes ethylene glycol, propylene glycol and butylene glycol of which propylene glycol is preferred. Glycerin is the preferred C1-10 trialcohoL A C1-10 monoalcohol is preferred for the purification. One most preferred C1-10 monoalcohol is isopropanol
The ratio of alcohol, such as isopropanol, to water is between 1:5 and 5:1. Preferably, when the alcohol is isopropanol, the ratio of isopropanol to water is 1:1. The compound of Formula XI is dissolved in a 1:1 mixture of isopropanol and water heated to the reflux point of the mixture. The solution is clarified by filtration with active carbon and a filter aid, then cooled to about 10 - 30oC and the purified compound of Formula XI crystallizes from solution. Preferably, the solution is cooled to about 20 - 25°C and the purified compound of Formula XI crystallizes from solution.

In a preferred embodiment when Florfenicol is the desired end product, the purified compound corresponding to Formula XI is the compound of Formula 1,
In another preferred embodiment, the process corresponding to the invention includes the steps of:
a) reacting a compound of Formula VI in a vessel with a reducing agent in an alcoholic solvent to form an aminodiol compound of Formula VII;
b) reacting the aminodiol compound of Formula VII in the vessel without isolation {i.e., in sHu) with an oxazolidlne forming agent to form a compound of Formula VIII;
c) reacting the compound of Formula VII lin the vessel without isolation (i.e., in situ) with a third N-acylating agent to form an oxazolidlne protected aminodiol compound of Formula XII:

wherein:
R1, R2. R3
and R7 are as defined above. Preferably, R7 is CH2CI, CHCI2. CCI3, CH2Br, CHBr2, CBr3, CH2F, CHF2, or CF3;
d) fluorinating the compound of Formula XII with a fluorinating agent in
the presence of an organic solvent to obtain a compound of Formula XIII:


wherein R1, R2, R3 and R7 are as defined above;
e) selectively hydrolyzing the compound of Fomnula XIII with an acid or base catalyst to fomn the compound of Formula XI; and
f) If necessary, purifying the compound of Formula XI with a mixture of a C1-10 alkyl mono, di or tri alcohol and water to form the pure compound of Formula XI.
In the preferred embodiment described above, there are certain preferred aspects of the invention. One preferred aspect is that after the compound of Formula VIII is made it is reacted preferably in the same vessel {i.e., in situ) with a suitable third N-acylating compound. Some preferred third N-acylating compounds are of the fonmula R6COR7 wherein R6 and R7 are as defined above. In a preferred embodiment, R6 is CI and R7 is CH2CI, CHCI2. CCI3, CH3Br, CHBr2, CBr3, CH2F. CHF2, or CF3.
Some preferred third N-acylating agents include alkylhaloacetic acid derivatives. A non-limiting list includes reagents such as methyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride, methylchloroacetate, ethylchloroacetate, chloroacetylchloride, methyltrichloroacetate. ethyltrichloroacetate, trichloroacetylchloride, methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride, methylfiuoroacetate, ethylfluoroacetate, fluoroacetylchloride, methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride, dichloroacetylbromide, difluoroacetylbromide, acetylchloride and acetylbromide.
In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XII is the compound of Formula Xlla:

In a preferred embodiment, a base such as potassium carbonate, sodium carbonate, trimethylamine or triethyiamine is added in a molar equivalent ratio to the compound of Formula Villa of about 1:1 to 1:3. The preferred base is potassium

carbonate or triethylamine and the preferred molar equivalent ratio is about 1.1 to 1. The preferred N-acylating agent dichloroacetyl chloride is added in a molar ratio to the compound of Formula Villa of about 1:1 to 3:1 with the prefen-ed ratio being 1,1:1. Reaction temperature is about 20 - 30oC and the reaction completes in about 2-4 hours.
After the oxazolidine protected aminodiol compound of Formula XII has been prepared, It can be used in the synthesis of Florfenicol and related compounds. Thus, in a further aspect of the invention, the inventive process continues by fluorinating the compound of Formula XII:

wherein Ri, R2. Rsand R7 are as defined above, with a fluorinatlng agent, as previously defined, in the presence of an organic solvent, as previously defined, to obtain a compound of Formula Xiil:

wherein R1, R2, R3 and R7 are as defined above.
In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XIII is specifically the compound of Formula Xllla:


After the compound of Formula XIII has been made, it is selectively hydrolyzed with acid or base catalyst to form the compound of Formula XI.
A wide range of acid catalysts can be employed in carrying out the process of the invention. A non-limiting list of suitable acid catalysts include inorganic acids like dilute aqueous hydrochloric acid, sulfuric acid, or phosphoric acid or organic acids like methanesulfonic acid or p-toluene sulfonic acid, One preferred acid catalyst is p-toluene sulfonic acid. Similarly, a wide range of basic catalysts can be employed in carrying out the process of the invention. A non-limiting list of suitable basic catalysts include inorganic bases such as LiOH. NaOH, KOH, LiaCO3, Na2CO3, K2CO3 or organic bases such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide. One preferred basic catalyst is K2CO3. The selective hydrolyzing step is preferably carried out be heating the compound of Formula XIII with p-toluene sulfonic acid in a mixture of an organic solvent and water at a temperature below 80''C. One preferred organic solvent is methylene chloride. Other suitable selective hydrolyzing steps will be apparent to those of ordinary skill.
In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XI is the compound of Formula I:


After the compound of Formula XI is made and if necessary, it can optionally be purified by the process as described above. In a preferred embodiment when Florfenicol is the desired end product, the purified compound corresponding to Formula XI is the compound of Formula I.
EXAMPLES
The following preparative examples of preferred novel derivatives serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention.
Example 1
Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]"1,3-oxazolidine (Compound II)
(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)phenyll"1,3"propandiol (Compound VII: Ri 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 VII!: Ri 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 crude product Filtration, washing with water (250 mL) then drying yields (4R,5R)-3-
acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II),
Example 2
Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II)

(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. Filtration, washing with water (200 mL) then drying yields (4R,5R)"3-acetyl"2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyI]-1,3-oxazolidine (Compound II).
Example 3
Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyll"1,3-oxazolidine (Compound 11)
(2S,3R)-Ethyl-2-amino-3-t4-(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-(methylsuIfonyl)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-hydroxymethyI-5-[4-(methylsuIfonyl)phenyl]-1,3-oxazolidine (Compound VIII: Ri 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) at 20 - 25'°C for 2 -- 4 hours then addition of water (650 mL) precipitates the crude product. Filtration, washing with water (300 mL) then drying yields (4R,5R)-3-
acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II).

{methyl-sulfQnyI)phenyI]-1-propanol (Florfenicol).

Example 8

(1S, SR)-3-acetyl-2,2-dimethyl-4-fluoromethyl'5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl; R2, R3 and R4 are methyl) (50.0 g, 0 1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90 0.1 mere over about 1 hour. Washing with methylene chloride (200 mL), adjusting

Example 14
Freparation of (1R,2S)-2-dichloroacetamiclo-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol)
(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyI-5-[4-(methyisulfonyl)phenyll-1,3-oxazolidine (Compound Xllla) (60.5 g, 0.1519 moles) selectively hydrolyses in methylene chloride (300 mL) and water (100 mL) containing p-toluene sulfonic acid at 60°C over several hours. Removal of the methylene chloride by distillation and cooling to 20 - 256°C precipitates the product. Filtration, washing with water (100 mL and toluene (100 mL) then drying yields (1R,2S)-2-dichioroacetamido-3-fluoro-1-{4-( methylsulfonyl)phenyl]-1 -propanol (Florfenicol).

What is claimed is:
1. A process for preparing a compound of Formula XI:

wherein:
R1 is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chioro, acetyl, benzyl, phenyl, halo substituted phenyl, C1-6 alkyl, C1-6 haloalkyi, C3.8 cycloalkyi, C2.6 alkenyl, C2.6 alkynyl, C^,Q alkoxy, C1-6 aralkyi, C2.6 aralkenyl, or C2-6 heterocyclic group; and
R7 is hydrogen, C1-6 alkyl, Ci-e haloalkyi, C1-6 dihaloalkyl, C1-6 trihaloalkyl, C3-8 cycloalkyi, C3.B cyclohaloalkyi, C3-6 cyclodihaloalkyi, C3.6 cyclotrihaloalkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 alkoxy, C1-6 aralkyi, C2-6 aralkenyl, C2-6 heterocyclic, benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, C1-6 alkyl or C1-6 alkoxy comprising:
a) reacting a compound of Formula Vl
wherein:
R1 is as defined above;
R5 is hydrogen, C1-6 alkyl, C3-8 cycloalkyi, benzyl, phenyl or C1-6 alkylphenyl, in a vessel with a reducing agent in an alcoholic solvent to form an aminodiol compound of Formula VII;


wherein R1 is as defined above;
b) reacting the aminodiol compound of Formula VII in situ with an
oxazolidine forming reagent to form a compound of Formula Vlll
wherein:
R1 is as defined above;
R2 is hydrogen, C1-6 alkyl, C1-6haloalkyl, C1-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 aralkyl, C2-6 aralkenyl, aryl, or C2.6 heterocyclic group; and
R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl. C3.8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 aralkyl, C2-6 aralkenyl, aryl or C2-6 heterocyclic group;
c) reacting the compound of Formula Vlll in situ with a third N-acylating
agent to form an oxazolidine protected aminodiol compound of Formula XII


wherein:
R1.R2, R3 and R7 are as defined above;
d) fluorinating the compound of Formula XII with a fluorinating agent in
the presence of an organic solvent to obtain a compound of Formula XIII

wherein:
R1, R2, R3 and R7 are as defined above; and
e) selectively hydrolyzing the compound of Formula XIII with an acid or
base catalyst to form a compound of Formula XI.
1, The process of claim 1, wherein R1 is methylthio, methylsulfoxy, or methylsulfonyl
3. The process of claim 2, wherein R1 is methylsulfonyl.
4. The process of claim 1, wherein R2 and R3 are hydrogen, methyl, ethyl or propyl
5. The process of claim 4, wherein R2 and R3 are methyl.
6. The process of claim 1, wherein R5 is methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl.
7. The process of claim 1, wherein the compound of Formula VI is


8. The process of claim 1, wherein the compound of Formula VI is

9. The process of claim % wherein the reducing agent is selected from the group consisting of NaBH4, KBH4, Ca(BH4)2, and LiBH4 and mixtures thereof.
10. The process of claim 9, wherein the reducing agent is KBH4.
11. The process of claim 10, wherein the molar ratio of KBH4 to the compound of Formula VI is between about 1:1 and 2:1.
12. The process of claim 11, wherein the molar ratio of KBH4 to the compound of Formula VI is about 1.5:1.
13. The process of claim 9, wherein the reduction is carried out at a temperature below 60^C.
14. The process of claim 13, wherein the reduction is complete within 6 hours.
15. The process of claim 1, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, ethylene glycol, glycerin and mixtures thereof.
16. The process of claim 15, wherein the solvent is methanol or ethanol.

17. The process of claim 16, wherein the solvent is methanol.
18. The process of claim 1, wherein the compound of Formula VII is

19. The process of claim 1, wherein the oxazolidine forming solvent is selected from toluene, xylene, hexanes or mixtures thereof
20. The process of claim 19, wherein the oxazolidine forming solvent is toluene.
21. The process of claim 20, wherein the ratio of toluene to methanol is between 0.5:1 and 3:1.
22. The process of claim 21, wherein the ratio of toluene to methanol is about 1:1.
23. The process of claim 1, wherein the oxazolidine forming reagent is selected from the group consisting of formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixtures thereof.
24. The process of claim 23, wherein the oxazolidine forming reagent is acetone.
25. The process of claim 24, wherein the ratio of acetone to toluene is between about 0,5:1 and 3:1.
26. The process of claim 25, wherein the ratio of acetone to toluene is about 1:1.

21, The process of claim 1, wherein the oxazolidine promoting base is selected from the group consisting of potassium carbonate, sodium carbonate, trimethylamine and triethylamine.
28. The process of claim 27, wherein the oxazolidine promoting base is potassium carbonate or triethylamine,
29. The process of claim 1, wherein the compound of Formula VIII is

30. The process of claim 29, wherein the compound of Formula VIII is
31. The process of claim 1» wherein the third N-acylating agent is of the formula: formula R6 COR7 wherein:
R6 is halo or C1-6 alkoxy; and
R7 is hydrogen, C1-6 alkyl, C1-6 haloalkyl. C1-6 dihaloalkyl, C1-6 trihaloalkyl, C3.8 cycloalkyl, C3.B cyclohaloalkyl, C3.8 cyclodihaioalkyl, C3.8 cyclotrihaloalkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 alkoxy. C1-6 aralkyl, C2.6 aralkenyl, C2-6 heterocyclic, benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, C1-6 alkyl or C1-6 alkoxy.

32. The process of claim 31, wherein R6 is CI, Br, methoxy or ethoxy.
33. The process of claim 32, wherein R6 is Cl.
34. The process of claim 31, wherein R7 is CH2CI, CHCI2, CCI3, CHoBr, CHBrz. CBr3,CH2F, CHF2, orCFs.
35. The process of claim 34, wherein R? is CHCI2.
36. The process of claim 31, wherein the third N-acylatating agent is selected from the group consisting of methyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride, methylchloroacetate, ethylchloroacetate, chloroacetylchloride, methyltrichloroacetate, ethyltrichloroacetate, trichloroacetylchloride, methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride, methylfluoroacetate, ethylfluoroacetate, fluoroacetylchloride, methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride, dichloroacetylbromide, difluoroacetylbromide, acetylchloride and acetylbromide and mixtures thereof.
37. The process of claim 36, wherein the third N-acylating agent is methyldichloroacetate or dichloroacetylchloride.
38. The process of claim 37, wherein the third N-acylating agent is dichloroacetylchloride.
39. The process of claim 1, wherein the third N-acylating base is selected from the group consisting of potassium carbonate, sodium carbonate, trimethylamlne and triethylamine.
40. The process of claim 39, wherein the third N-acylating base is potassium carbonate or triethyiamine.

41. The process of claim 40, wherein the molar equivalent ratio of the third N-acylating base to the compound of Formula VIII is between 1:1 and 3:1.
42. The process of claim 41, wherein the molar equivalent ratio of the third N-acylating base to the compound of Fonnula VIII is about 1.1:1.
43. The process of claim 42, wherein the molar ratio of dichloroacetyl chloride to the compound of Formula VIII is between about 1:1 and 3:1.
44. The process of claim 43, wherein the molar ratio of dichloroacetyl chloride to the compound of Fomiula Vlllis about 1.1 to 1.
45. The process of claim 36, wherein the third N-acylation step is carried out at a temperature between 20 - SO^C,
46. The process of claim 45, wherein the third N-acylation reaction is complete within 2-4 hours.
47. The process of claim 1, wherein R7 is CH2CI, CHCI2, CCI3, CH2Br, CHBr2, CBrs, CH2F, CHF2, or CF3.
48. The process of claim 47, wherein R7 is CHCI2 or CHF2.
49. The process of claim 48, wherein R7 is CHCI2.
50. The process of claim 1, wherein the compound of Formula XII is;

51. The process of claim 50, wherein the compound of Formula Xli is:


54. The process of claim 1, wherein the fiuorinating agent is selected from the group consisting of N-(2-chlorO"1.1,24rifluoroethyl)diethylamine, N-(2-chloro-1,1,2-trifluor-oethyl)dimethylamine, N-(2-chloro-1,1,2-trifluoroethyI)dipropylamine, N-(2-chloro-1,1,2-trifluoroethyl)pyrrolidine, N-(2-chloro-1,1,2-trifluoroethyl)-2-methylpyrrolidine, N-(2-chloro-1,1,2-trifluoroethyl)-4-methylpipera2ine, N-(2-chloro-1,1,2-trifluoroethyl)- morpholine, N-(2-chloro-1,1,2-trifluoroethy[)piperidine, 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethyiamlno) sulfur trifluoride, Bis-(2-methoxyethyl)aminosulfur trifluoride, N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) and mixtures thereof.

55. The process of claim 54, wherein the fluorinating agent is N,N-diethyl-1,1,2,3,3,3-hexafluoro-1 -propanamine.
56. The process of claim 55, wherein the molar ratio of N,N"diethyI-1,1,2,3,3,3-hexafluoro-1-propanamine to the compound of Formula XII is between about 1:1 and 2:1.
57. The process of claim 56, wherein the molar ratio of N,N-dlethyl-1,1,2,3,3,3-hexafluoro-1-propanamine to the compound of Formula XII is about 1.5:1.
58. The process of claim 57, wherein the fluorinating step is canried out at a temperature of from about 80°C to about 110°C and at a pressure of about 60 psi.
59. The process of claim 1, wherein the organic solvent is selected from the group consisting of 1,2-dichloroethane, methylene chloride, chloroform, chlorobenzene, chlorinated hydrocarbons and mixtures thereof.
60. The process of claim 59, wherein the organic solvent is methylene chloride.
61. The process of claim 1, wherein the compound of Formula XIII is

62. The process of claim 61, wherein the compound of Formula Xlli is:


63. The process of claim 61, wherein the compound of Formula Xlll is

64. The process of claim 63. wherein the compound of Formula Xlll is

65. The process of claim 1, wherein the compound of Formula XI is:

66. The process of claim 65, wherein the compound is Florfenicol


67. The process of claim 1, wherein the acid catalyst is dilute aqueous hydrochloric acid, sulfuric acid, or phosphoric acid, methanesulfonic acid or p-toluene sulfonic acid.
68. The process of claim 67, wherein the acid catalyst is p-toluene sulfonic acid.
69. The process of claim 1, wherein the base catalyst is LiOH, NaOH, KOH, U2CO3. Na2CO3, K2CO3, sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide.
70. The process of claim 69, wherein the base catalyst is K2CO3.
71. The process of claim 1, wherein the temperature of the selective hydrolysis is below 80°C.

72. The process of claim 1, wherein methylene chloride is the organic solvent for the selective hydrolysis.
73. The process of claim 1, wherein the compound of Formula XI is purified with a mixture of a C1-10 alkyl mono, di or tri alcohol and water to form the pure form of a compound of Formula XI.
74. The process of claim 73, wherein the purification is carried out in a mixture of methanol, ethanol, propanol, iso-propanol, butanol, sec-butanol. t-butanol, pentanol, ethylene glycol, propylene glycol, butylene glycol or glycerin and water.

75. The process of claim 74, wherein the purification is earned out in a mixture of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, or pentanol and water.
76. The process of claim 75, wherein the purification is carried out in a mixture of isopropanol and water.
77. The process of claim 76, wherein the ratio of isopropanol to water is between
1:5 and 5:1.
78. The process of claim 77, wherein the ratio of Isopropanol to water is 1:1.
79. The process of claim 78, wherein the dissolution temperature for purification is
the reflux point of 1:1 isopropanol and water.
80. The process of claim 73, wherein the purification reaction is cooled to 10 -
30°C to crystallize the desired compound.
81. The process of claim 80, wherein the purification reaction is cooled to about
20 - 25°C to crystallize the desired compound.