U.S. patent application number 11/515278 was filed with the patent office on 2007-03-08 for process for preparing oxazolidine protected aminodiol compounds useful as intermediates to florfenicol.
This patent application is currently assigned to Schering-Plough Animal Health Corp.. Invention is credited to James C. Towson.
Application Number | 20070055067 11/515278 |
Document ID | / |
Family ID | 37684114 |
Filed Date | 2007-03-08 |
United States Patent
Application |
20070055067 |
Kind Code |
A1 |
Towson; James C. |
March 8, 2007 |
Process for preparing oxazolidine protected aminodiol compounds
useful as intermediates to Florfenicol
Abstract
An improved method of preparing oxazolidine protected aminodiol
compounds is disclosed. These compounds are useful intermediates in
processes for making Florfenicol.
Inventors: |
Towson; James C.;
(Flemington, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering-Plough Animal Health
Corp.
|
Family ID: |
37684114 |
Appl. No.: |
11/515278 |
Filed: |
August 31, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60714685 |
Sep 7, 2005 |
|
|
|
Current U.S.
Class: |
548/215 ;
564/123 |
Current CPC
Class: |
C07C 317/32 20130101;
C07D 263/06 20130101; C07D 263/04 20130101; C07C 315/04 20130101;
C07C 315/04 20130101 |
Class at
Publication: |
548/215 ;
564/123 |
International
Class: |
C07D 263/02 20060101
C07D263/02 |
Claims
1. A process for preparing a compound of Formula XI: ##STR40##
wherein: R.sub.1 is hydrogen, methylthio, methylsulfoxy,
methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy,
fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl,
phenyl, halo substituted phenyl, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl,
or C.sub.2-6 heterocyclic group; and R.sub.7 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 dihaloalkyl, C.sub.1-6
trihaloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cyclohaloalkyl,
C.sub.3-8 cyclodihaloalkyl, C.sub.3-8 cyclotrihaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl,
C.sub.2-6 aralkenyl, C.sub.2-6 heterocyclic, benzyl, phenyl or
phenyl alkyl where the phenyl ring may be substituted by one or two
halogens, C.sub.1-6 alkyl or C.sub.1-6 alkoxy comprising: a)
reacting a compound of Formula VI ##STR41## wherein: R.sub.1 is as
defined above; R.sub.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, benzyl, phenyl or C.sub.1-6 alkylphenyl, in a vessel
with a reducing agent in an alcoholic solvent to form an aminodiol
compound of Formula VII; ##STR42## wherein R.sub.1 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
VIII ##STR43## wherein: R.sub.1 is as defined above; R.sub.2 is
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8
cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy,
C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, aryl, or C.sub.2-6
heterocyclic group; and R.sub.3 is hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6
aralkenyl, aryl or C.sub.2-6 heterocyclic group; c) reacting the
compound of Formula VIII in situ with a third N-acylating agent to
form an oxazolidine protected aminodiol compound of Formula XII
##STR44## wherein: R.sub.1, R.sub.2, R.sub.3 and R.sub.7 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 ##STR45## wherein: R.sub.1, R.sub.2,
R.sub.3 and R.sub.7 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.
2. The process of claim 1, wherein R.sub.1 is methylthio,
methylsulfoxy, or methylsulfonyl.
3. The process of claim 2, wherein R.sub.1 is methylsulfonyl.
4. The process of claim 1, wherein R.sub.2 and R.sub.3 are
hydrogen, methyl, ethyl or propyl.
5. The process of claim 4, wherein R.sub.2 and R.sub.3 are
methyl.
6. The process of claim 1, wherein R.sub.5 is methyl, ethyl,
n-propyl, isopropyl, butyl, t-butyl, or pentyl.
7. The process of claim 1, wherein the compound of Formula VI is
##STR46##
8. The process of claim 1, wherein the compound of Formula VI is
##STR47##
9. The process of claim 1, wherein the reducing agent is selected
from the group consisting of NaBH.sub.4, KBH.sub.4,
Ca(BH.sub.4).sub.2, and LiBH.sub.4 and mixtures thereof.
10. The process of claim 9, wherein the reducing agent is
KBH.sub.4.
11. The process of claim 10, wherein the molar ratio of KBH.sub.4
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 KBH.sub.4
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.degree. 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
##STR48##
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.
27. 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
##STR49##
30. The process of claim 29, wherein the compound of Formula VIII
is ##STR50##
31. The process of claim 1, wherein the third N-acylating agent is
of the formula: formula R.sub.6COR.sub.7 wherein: R.sub.6 is halo
or C.sub.1-6 alkoxy; and R.sub.7 is hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 dihaloalkyl, C.sub.1-6 trihaloalkyl,
C.sub.3-8 cycloalkyl, C.sub.3-8 cyclohaloalkyl, C.sub.3-8
cyclodihaloalkyl, C.sub.3-8 cyclotrihaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6
aralkenyl, C.sub.2-6 heterocyclic, benzyl, phenyl or phenyl alkyl
where the phenyl ring may be substituted by one or two halogens,
C.sub.1-6 alkyl or C.sub.1-6 alkoxy.
32. The process of claim 31, wherein R.sub.6 is Cl, Br, methoxy or
ethoxy.
33. The process of claim 32, wherein R.sub.6 is Cl.
34. The process of claim 31, wherein R.sub.7 is CH.sub.2Cl,
CHCl.sub.2, CCl.sub.3, CH.sub.2Br, CHBr.sub.2, CBr.sub.3,
CH.sub.2F, CHF.sub.2, or CF.sub.3.
35. The process of claim 34, wherein R.sub.7 is CHCl.sub.2.
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, trimethylamine and triethylamine.
40. The process of claim 39, wherein the third N-acylating base is
potassium carbonate or triethylamine.
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 Formula 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 Formula VIII is about
1.1 to 1.
45. The process of claim 36, wherein the third N-acylation step is
carried out at a temperature between 20-30.degree. 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 R.sub.7 is CH.sub.2Cl,
CHCl.sub.2, CCl.sub.3, CH.sub.2Br, CHBr.sub.2, CBr.sub.3,
CH.sub.2F, CHF.sub.2, or CF.sub.3.
48. The process of claim 47, wherein R.sub.7 is CHCl.sub.2 or
CHF.sub.2.
49. The process of claim 48, wherein R.sub.7 is CHCl.sub.2.
50. The process of claim 1, wherein the compound of Formula XII is:
##STR51##
51. The process of claim 50, wherein the compound of Formula XII
is: ##STR52##
52. The process of claim 50, wherein the compound of Formula XII
is: ##STR53##
53. The process of claim 52, wherein the compound of Formula XII
is: ##STR54##
54. The process of claim 1, wherein the fluorinating agent is
selected from the group consisting of
N-(2-chloro-1,1,2-trifluoroethyl)diethylamine,
N-(2-chloro-1,1,2-trifluor-oethyl)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-1,1,2-trifluoroethyl)-morpholine,
N-(2-chloro-1,1,2-trifluoroethyl)piperidine,
1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethylamino)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-diethyl-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-diethyl-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
carried out at a temperature of from about 80.degree. C. to about
110.degree. 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
##STR55##
62. The process of claim 61, wherein the compound of Formula XIII
is: ##STR56##
63. The process of claim 61, wherein the compound of Formula XIII
is ##STR57##
64. The process of claim 63, wherein the compound of Formula XIII
is ##STR58##
65. The process of claim 1, wherein the compound of Formula XI is:
##STR59##
66. The process of claim 65, wherein the compound is Florfenicol
##STR60##
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, Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
sodium methoxide, sodium ethoxide, potassium methoxide and
potassium ethoxide.
70. The process of claim 69, wherein the base catalyst is
K.sub.2CO.sub.3.
71. The process of claim 1, wherein the temperature of the
selective hydrolysis is below 80.degree. 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 C.sub.1-10 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 carried
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.degree. C. to crystallize the desired compound.
81. The process of claim 80, wherein the purification reaction is
cooled to about 20-25.degree. C. to crystallize the desired
compound.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a non-provisional application that
claims priority under 35 U.S.C. .sctn. 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
##STR1##
[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-(methylsulfo-
nyl)phenyl]ethyl]acetamide.
[0005] Commonly-assigned U.S. Pat. No. 5,663,361, the disclosure of
which is incorporated herein by reference, describes the synthesis
of Florfenicol intermediates and their use in processes for making
Florfenicol. The primary advantage discussed therein is that the
process eliminated the prior art's requirement to isolate the
aminodiol sulfone (ADS) from the reaction vessel before proceeding
with the Florfenicol synthesis.
[0006] More recently, U.S. Patent 2005/0075506 A1 described a
process for preparing a compound of Formula II that is useful as an
intermediate in the synthesis of Florfenicol. ##STR2##
[0007] The process called for reacting the hydrochloride salt of an
optically pure aminodiol compound of Formula III with acetone
followed by acetyl chloride to give a compound of Formula II. The
compound of Formula II is then reacted further to give Florfenicol
of Formula I. ##STR3## 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.
[0008] Another major drawback of the process disclosed in
2005/0075506 A1 is the requirement to hydrolyze the oxazolidine and
the N-acetyl group of Formula IXa; ##STR4## to generate a compound
of Formula Xa; ##STR5## followed by acylating, with a second
N-acylating agent, to form a compound of Formula I.
[0009] The present invention addresses these shortcomings and
provides alternative methods of preparing useful intermediates
included in the synthesis of Florfenicol.
SUMMARY OF THE INVENTION
[0010] In one embodiment, the present invention includes a process
for preparing an oxazolidine protected aminodiol compound of
Formula V: ##STR6##
[0011] wherein:
[0012] R.sub.1 is hydrogen, methylthio, methylsulfoxy,
methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy,
fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl,
phenyl, halo substituted phenyl, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl,
or C.sub.2-6 heterocyclic group;
[0013] R.sub.2 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, aryl, or
C.sub.2-6 heterocyclic group;
[0014] R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, aryl or
C.sub.2-6 heterocyclic group; and
[0015] R.sub.4 is hydrogen, OH, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, benzyl, phenyl or C.sub.1-6
phenylalkyl group, where the phenyl ring may be substituted by one
or two halogens, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy.
[0016] In another preferred embodiment, the present invention
includes a process for preparing an oxazolidine protected aminodiol
compound of Formula XII: ##STR7##
[0017] wherein:
[0018] R.sub.1, R.sub.2 and R.sub.3 are as defined above; and
[0019] R.sub.7 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 dihaloalkyl, C.sub.1-6 trihaloalkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 cyclohaloalkyl, C.sub.3-8 cyclodihaloalkyl,
C.sub.3-8 cyclotrihaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, C.sub.2-6
heterocyclic, benzyl, phenyl or phenyl alkyl where the phenyl ring
may be substituted by one or two halogens, C.sub.1-6 alkyl or
C.sub.1-6 alkoxy. Preferably, R.sub.7 is CH.sub.2Cl, CHCl.sub.2,
CCl.sub.3, CH.sub.2Br, CHBr.sub.2, CBr.sub.3, CH.sub.2F, CHF.sub.2,
or CF.sub.3.
[0020] In one embodiment, the process includes the steps of:
[0021] a) reacting a compound of Formula VI: ##STR8##
[0022] wherein:
[0023] R.sub.1 is as defined above and R.sub.5 is hydrogen,
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, benzyl, phenyl or C.sub.1-6
phenylalkyl, in a vessel with a reducing agent in an alcoholic
solvent to form an aminodiol compound of Formula VII: ##STR9##
[0024] wherein:
[0025] R.sub.1 is as defined above;
[0026] b) reacting the aminodiol compound of Formula VII in the
vessel without isolation (i.e., in situ) with an oxazolidine
forming reagent to form a compound of Formula VIII: ##STR10##
[0027] wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above;
and
[0028] 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.
[0029] In another preferred embodiment, the process includes the
steps of:
[0030] 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;
[0031] b) reacting the aminodiol compound of Formula VII in the
vessel without isolation (i.e., in situ) with an oxazolidine
forming agent to form the compound of Formula VIII;
[0032] c) reacting the compound of Formula VIII in the vessel
without isolation (i.e., in situ) with an N-acylating agent to form
an oxazolidine protected aminodiol compound of Formula XII;
[0033] d) fluorinating the compound of Formula XII with a
fluorinating agent in the presence of an organic solvent to obtain
the compound of Formula XIII: ##STR11##
[0034] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined
above;
[0035] e) selectively hydrolyzing the compound of Formula XIII with
an acid or base catalyst to form the compound of Formula XI:
##STR12##
[0036] wherein R.sub.1 and R.sub.7 are as defined above; and
[0037] f) if necessary, purifying the compound of Formula XI with a
mixture of a C.sub.1-10 alkyl mono, di or tri alcohol and water to
form the pure compound of Formula XI.
[0038] Applicants have now surprisingly found significant
processing advantages for forming the oxazolidine protected
aminodiol compounds of Formula V and Formula XII. The compounds of
Formula V, or specifically Formula II, are obtained when an ester
precursor to the aminodiol free base compound of Formula III are
used as starting materials. Such esters generally correspond to
Formula VI, and the ester of Formula IV is one particularly
preferred ester: ##STR13##
[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.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0040] When utilized in the present specification and in the
appended claims, the terms listed herein below, unless otherwise
indicated, are defined as follows:
[0041] The term "alcoholic solvent" includes C.sub.1 to C.sub.10
alcohols such as methanol and ethanol and mixtures thereof, C.sub.2
to C.sub.10 dialcohols such as ethylene glycol and C.sub.1 to
C.sub.10 trialcohols such as glycerin. Alternatively, the alcoholic
solvent can be admixed with any suitable cosolvent. Such cosolvents
can include other solvents which are miscible with the alcoholic
solvent such as C.sub.4 to C.sub.10 alkanes, aromatic solvents such
as benzene, toluene, xylenes, halobenzenes such as chlorobenzene,
and ethers such as diethylether, tert-butylmethylether,
isopropylether and tetrahydrofuran, or mixtures of any of the above
solvents or cosolvents.
[0042] The term "alkyl" means a straight or branched alkyl such as
methyl, ethyl, propyl, or sec-butyl. Alternatively, the number of
carbons in alkyl may be specified. For example, "C.sub.1 to C.sub.6
alkyl" means an "alkyl" as described above containing 1 to 6 carbon
atoms. "Haloalkyl" means an "alkyl" as described above wherein one
or more hydrogens are replaced by halo.
[0043] The term "aryl" means phenyl, or phenyl substituted by
C.sub.1 to C.sub.6 alkyl or halo.
[0044] "Substituted benzyl" means benzyl substituted by C.sub.1 to
C.sub.6 alkyl or halo.
[0045] The term "halo" means fluoro, chloro, bromo or iodo.
[0046] The term "halo aryl" means phenyl substituted by halo.
[0047] In one aspect of the invention, there is provided a process
for preparing an oxazolidine protected aminodiol compound of
Formula V: ##STR14##
[0048] wherein:
[0049] R.sub.1 is hydrogen, methylthio, methylsulfoxy,
methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy,
fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl,
phenyl, halo substituted phenyl, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl,
or C.sub.2-6 heterocyclic group;
[0050] R.sub.2 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, aryl, or
C.sub.2-6 heterocyclic group;
[0051] R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, aryl or
C.sub.2-6 heterocyclic group; and
[0052] R.sub.4 is hydrogen, OH, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, benzyl, phenyl or C.sub.1-6
phenylalkyl group, where the phenyl ring may be substituted by one
or two halogens, C.sub.1-6 alkyl or C.sub.1-6 alkoxy.
[0053] The compounds corresponding thereto are useful intermediates
in the formation of Florfenicol and related compounds.
[0054] One preferred process corresponding to the invention
includes the steps of:
[0055] a) reacting a compound of Formula VI: ##STR15##
[0056] wherein:
[0057] R.sub.1 is as defined above and R.sub.5 is hydrogen,
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, benzyl, phenyl or C.sub.1-6
alkylphenyl, in a vessel with a reducing agent in an alcoholic
solvent to form an aminodiol compound of Formula VII: ##STR16##
[0058] wherein R.sub.1 is as defined above;
[0059] b) reacting the aminodiol compound of Formula VII in the
vessel without isolation (i.e., in situ) with an oxazolidine
forming reagent to form a compound of Formula VIII: ##STR17##
[0060] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined
above; and
[0061] 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:
##STR18##
[0062] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined
above.
[0063] Within the general process described above, there are
certain currently preferred aspects of the invention:
[0064] R.sub.1 is methylthio, methylsulfoxy, or methylsulfonyl.
More preferably, R.sub.1 is methylsulfonyl;
[0065] R.sub.2 and R.sub.3 are hydrogen, methyl, ethyl or propyl.
More preferably, R.sub.2 and R.sub.3 are methyl;
[0066] R.sub.4 is a methyl, ethyl, propyl or isopropyl group. More
preferably, R.sub.4 is methyl; and
[0067] R.sub.5 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 without undue
experimentation.
[0068] One preferred ester compound corresponding to Formula VI is
##STR19##
[0069] In another aspect of the invention, the ester compound of
Formula VI is ##STR20##
[0070] In still further aspects, the esters correspond to:
##STR21##
[0071] wherein R.sub.5 is as defined above.
[0072] In a more preferred embodiment when Florfenicol is the
desired end product, the compound corresponding to Formula VI is
the compound of Formula IV.
[0073] 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.
[0074] 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 NaBH.sub.4, KBH.sub.4,
Ca(BH.sub.4).sub.2, and LiBH.sub.4 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 KBH.sub.4.
[0075] The molar ratio of reducing agent, such as KBH.sub.4, to the
compound of Formula IV is between about 1:1 and about 2:1.
Preferably, when the reducing agent is KBH.sub.4, the molar ratio
of KBH.sub.4 to the compound of Formula IV is about 1.5:1 and the
preferred solvent is methanol. This reduction can be carried out at
a temperature of about 30.degree. C. to about 80.degree. C. in
about 8 hours. Preferably, the temperature is below 60.degree. C.
and the time for the reaction to reach completion is under 6
hours.
[0076] In an alternative aspect of the invention, the artisan can
use reducing agents such as LiAlH.sub.4 or NaAlH.sub.4 when
anhydrous conditions are desired. In such situations, solvents like
ether or tetrahydrofuran can be used.
[0077] 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
##STR22##
[0078] In a preferred embodiment when Florfenicol is the desired
end product, the compound corresponding to Formula VIII is the
compound: ##STR23## 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.degree. C.
[0079] 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 R.sub.6COR.sub.4
[0080] wherein:
[0081] R.sub.4 is hydrogen, OH, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-8 cycloalkyl, benzyl, phenyl or C.sub.1-6
phenylalkyl group, where the phenyl ring may be substituted by one
or two halogens, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; and
[0082] R.sub.6 is halo, or C.sub.1-6 alkoxy.
[0083] Some more preferred first acylating agents include acetyl
chloride, acetyl bromide, propionyl chloride, propionyl bromide,
butyl chloride, methyl chloroformate, ethyl chloroformate, propyl
chloroformate and mixtures thereof.
[0084] In a preferred embodiment when Florfenicol is the desired
end product, the compound corresponding to Formula V is the
compound: ##STR24##
[0085] 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 molar 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.degree. C. and the reaction completes in about 2-4
hours.
[0086] 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: ##STR25##
[0087] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined
above, with a fluorinating agent in the presence of an organic
solvent to obtain a compound of Formula IX: ##STR26##
[0088] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined
above.
[0089] In one preferred aspect of this embodiment when Florfenicol
is the desired end product, the compound corresponding to Formula
IX is specifically: ##STR27##
[0090] Suitable fluorinating agents include, without limitation,
N-(2-chloro-1,1,2-trifluoroethyl)diethylamine,
N-(2-chloro-1,1,2-trifluoroethyl)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-1,1,2-trifluoroethyl)-morpholine,
N-(2-chloro-1,1,2-trifluoroethyl)piperidine,
1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethylamino)sulfur
trifluoride, Bis-(2-methoxyethyl)aminosulfur trifluoride,
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.
[0091] The molar ratio of the fluorinating agent such as
N,N-diethyl-1,1,2,3,3,3-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.degree. C. to about 110.degree.
C. and at a pressure of about 60 psi.
[0092] 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.
[0093] After the compound of Formula IX has been made, it is
hydrolyzed with acid to form the compound of Formula X:
##STR28##
[0094] wherein R.sub.1 is as defined above, preferably, R.sub.1 is
CH.sub.3SO.sub.2.
[0095] 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.degree. C. to about 105.degree. C. for about 60
minutes. Other suitable hydrolyzing steps will be apparent to those
of ordinary skill.
[0096] In one preferred aspect of this embodiment when Florfenicol
is the desired end product, the compound corresponding to Formula X
is: ##STR29##
[0097] 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: ##STR30##
[0098] wherein R.sub.1 is the same as above, preferably
CH.sub.3SO.sub.2; and
[0099] R.sub.7 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 dihaloalkyl, C.sub.1-6 trihaloalkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 cyclohaloalkyl, C.sub.3-8 cyclodihaloalkyl,
C.sub.3-8 cyclotrihaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 aralkyl, C.sub.2-6 aralkenyl, C.sub.2-6
heterocyclic benzyl, phenyl or phenyl alkyl where the phenyl ring
may be substituted by one or two halogens, C.sub.1-6 alkyl or
C.sub.1-6 alkoxy. Preferably, R.sub.7 is CH.sub.2Cl, CHCl.sub.2,
CCl.sub.3, CH.sub.2Br, CHBr.sub.2, CBr.sub.3, CH.sub.2F, CHF.sub.2,
or CF.sub.3. Thus, one preferred compound of Formula XI is:
##STR31##
[0100] wherein R.sub.7 is as defined above.
[0101] 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: ##STR32##
[0102] Suitable second N-acylating compounds are of the formula
R.sub.8COR.sub.7, wherein R.sub.7 is the same as that described
above and R.sub.8 is OH, halo or C.sub.1-6 alkoxy. Some more
preferred second N-acylating agents include dichloroacetic acid or
a reactive derivative thereof. A non-limiting list includes
reagents such as methyldichloroacetate, ethyldichloroacetate, or
dichloroacetylchloride.
[0103] The second N-acylation step is preferably carried out by
reacting the compound of Formula X in methanol with
methyldichloroacetate at a temperature of from about 20.degree. C.
to about 30.degree. C. for about 12 hours.
[0104] After the compound of Formula XI is made and if necessary,
the compound of Formula 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 C.sub.1-10
monoalcohols, C.sub.1-10 dialcohols and C.sub.1-10 trialcohols and
mixtures thereof. A non-limiting list of the C.sub.1-10
monoalcohols includes methanol, ethanol, propanol, isopropanol,
butanol, sec-butanol, t-butanol and pentanol. One preferred
C.sub.1-10 monoalcohol is isopropanol. A non-limiting list of the
C.sub.1-10 dialcohols includes ethylene glycol, propylene glycol
and butylene glycol of which propylene glycol is preferred.
Glycerin is the preferred C.sub.1-10 trialcohol. A C.sub.1-10
monoalcohol is preferred for the purification. One most preferred
C.sub.1-10 monoalcohol is isopropanol.
[0105] 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 10-30.degree. C. and the purified compound of Formula XI
crystallizes from solution. Preferably, the solution is cooled to
about 20-25.degree. C. and the purified compound of Formula XI
crystallizes from solution.
[0106] In a preferred embodiment when Florfenicol is the desired
end product, the purified compound corresponding to Formula XI is
the compound of Formula I.
[0107] In another preferred embodiment, the process corresponding
to the invention includes the steps of:
[0108] 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;
[0109] b) reacting the aminodiol compound of Formula VII in the
vessel without isolation (i.e., in situ) with an oxazolidine
forming agent to form a compound of Formula VIII;
[0110] c) reacting the compound of Formula VIII in the vessel
without isolation (i.e., in situ) with a third N-acylating agent to
form an oxazolidine protected aminodiol compound of Formula XII:
##STR33##
[0111] wherein:
[0112] R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined above.
Preferably, R.sub.7 is CH.sub.2Cl, CHCl.sub.2, CCl.sub.3,
CH.sub.2Br, CHBr.sub.2, CBr.sub.3, CH.sub.2F, CHF.sub.2, or
CF.sub.3;
[0113] 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: ##STR34##
[0114] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined
above;
[0115] e) selectively hydrolyzing the compound of Formula XIII with
an acid or base catalyst to form the compound of Formula XI;
and
[0116] f) if necessary, purifying the compound of Formula XI with a
mixture of a C.sub.1-10 alkyl mono, di or tri alcohol and water to
form the pure compound of Formula XI.
[0117] 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 formula R.sub.6COR.sub.7 wherein R.sub.6 and R.sub.7 are
as defined above. In a preferred embodiment, R.sub.6 is Cl and
R.sub.7 is CH.sub.2Cl, CHCl.sub.2, CCl.sub.3, CH.sub.2Br,
CHBr.sub.2, CBr.sub.3, CH.sub.2F, CHF.sub.2, or CF.sub.3.
[0118] 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, methylfluoroacetate, ethylfluoroacetate,
fluoroacetylchloride, methyltrifluoroacetate,
ethyltrifluoroacetate, trifluoroacetylchloride,
dichloroacetylbromide, difluoroacetylbromide, acetylchloride and
acetylbromide.
[0119] In a preferred embodiment when Florfenicol is the desired
end product, the compound corresponding to Formula XII is the
compound of Formula XIIa: ##STR35##
[0120] 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 VIIIa
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 VIIIa of about
1:1 to 3:1 with the preferred ratio being 1.1:1. Reaction
temperature is about 20-30.degree. C. and the reaction completes in
about 2-4 hours.
[0121] 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: ##STR36##
[0122] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined
above, with a fluorinating agent, as previously defined, in the
presence of an organic solvent, as previously defined, to obtain a
compound of Formula XIII: ##STR37##
[0123] wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined
above.
[0124] 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 XIIIa: ##STR38##
[0125] 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.
[0126] 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,
Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or organic
bases such as sodium methoxide, sodium ethoxide, potassium
methoxide and potassium ethoxide. One preferred basic catalyst is
K.sub.2CO.sub.3. 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.degree. C. One preferred organic solvent is
methylene chloride. Other suitable selective hydrolyzing steps will
be apparent to those of ordinary skill.
[0127] 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: ##STR39##
[0128] 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
[0129] 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)
[0130]
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propa-
noate (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.degree. C. to quantitatively yield
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol
(Compound VII: R.sub.1 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.degree. C. for 12-18 hours yields
(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxa-
zolidine (Compound VIII: R.sub.1 is methylsulfonyl and R.sub.2 and
R.sub.3 are methyl). Addition of potassium carbonate (19.0 g,
0.1914 moles) and acetyl chloride (30.0 g, 0.3828 moles) at
20-25.degree. 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)
[0131]
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propa-
noate (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.degree. C. to quantitatively yield
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol
(Compound VII: R.sub.1 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.degree. C. for 12-18 hours yields
(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxa-
zolidine (Compound VIII: R.sub.1 is methylsulfonyl and R.sub.2 and
R.sub.3 are methyl). Addition of triethylamine (44.5 g, 0.4402
moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25.degree.
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)phenyl-
]-1,3-oxazolidine (Compound II).
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-propa-
noate (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.degree. C. to quantitatively yield
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol
(Compound VII: R.sub.1 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.degree. C. for 10-16 hours
produces
(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxa-
zolidine (Compound VIII: R.sub.1 is methylsulfonyl and R.sub.2 and
R.sub.3 are methyl). Addition of triethylamine (81.3 g, 0.8039
moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25.degree.
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).
Example 4
Preparation of
(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phe-
nyl]-1,3-oxazolidine (Compound V: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl)
[0133]
(2S,3R)-Methyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-prop-
anoate (Compound VI: R.sub.1 is methylsulfonyl and R.sub.5 is
methyl) (75 g, 0.2744 moles) in 350 mL of methanol reacts with
sodium borohydride (16.6 g, 0.4390 moles) over 4-8 hours at
50-60.degree. C. to quantitatively yield
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol
(Compound VII: R.sub.1 is methylsulfonyl) (67.31 g, 0.2744 moles)
in solution. Addition of 20% hydrochloric acid and
2,2-dimethoxypropane (35.7 g, 0.3430 moles) with agitation at
25-35.degree. C. for 3-5 hours then addition of xylene (650 mL) and
heating to 75-85.degree. C. for a further 12-16 hours yields
(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxa-
zolidine (Compound VIII: R.sub.1 is methylsulfonyl and R.sub.2 and
R.sub.3 are methyl). Addition of triethylamine (52.1 g, 0.5145
moles) and propionyl chloride (31.7 g, 0.3430 moles) at
20-25.degree. C. for 2-4 hours then addition of water (625 mL)
precipitates the crude product. Filtration, washing with water (300
mL) then drying yields
(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)-ph-
enyl]-1,3-oxazolidine (Compound V: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl).
Example 5
Preparation of
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-
-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl; R.sub.2,
R.sub.3 and R.sub.4 are methyl)
[0134]
(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl-
)phenyl]-1,3-oxazolidine (Compound II) (75 g, 0.2291 moles) in
methylene chloride (525 ml) reacts with
N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent)
(76.7 g, 0.3437 moles) at 95-105.degree. C. for about 4 hours.
Cooling to 20-25.degree. C., addition to sodium hydroxide (6 g) in
water (2500 mL), separation of the methylene chloride layer,
distillation and replacement of methylene chloride by isopropanol
(750 mL), precipitates the desired product. Filtration, washing
with water (100 mL) and isopropanol (75 mL), then drying yields
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-
-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl; R.sub.2,
R.sub.3 and R.sub.4 are methyl).
Example 6
Preparation of
(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phen-
yl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl)
[0135]
(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfo-
nyl)phenyl]-1,3-oxazolidine (Compound V: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl) (70 g, 0.2050
moles) in methylene chloride (450 ml) reacts with
N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent)
(73.2 g, 0.328 moles) at 95-105.degree. C. for 2-4 hours. Cooling
to 20-25.degree. C., quenching with 25% aqueous sodium hydroxide
and water (2000 mL) and separation of the methylene chloride layer
gives a solution of
(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)p-
henyl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl) for use in the
next step.
Example 7
Preparation of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0136]
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)-
phenyl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl;
R.sub.2, R.sub.3 and R.sub.4 are methyl) (50.0 g, 0.1518 moles)
hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90
to 100.degree. C. over about 1 hour. Adjusting the pH to greater
than 12 by addition of sodium hydroxide and extraction with
methylene chloride (500 mL) yields
(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol
(Compound Xa) in solution. Methanol (100 mL) replaces methylene
chloride which distills off. Addition of methyl dichloroacetate
(65.1 g, 0.4554 moles) and triethylamine (16.1 g, 0.1594 moles)
with agitation for 12-16 hours at 20-25.degree. C. then addition of
water (175 mL) and toluene (100 mL) precipitates the product.
Filtration, washing with water (100 mL) and toluene (175 mL) then
drying yields
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methyl-sulfonyl)phenyl]-1-prop-
anol (Florfenicol).
Example 8
Preparation of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0137]
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)-
phenyl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl;
R.sub.2, R.sub.3 and R.sub.4 are methyl) (50.0 g, 0.1518 moles)
hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90
to 100.degree. C. over about 1 hour. Adjusting the pH to greater
than 12 by addition of sodium hydroxide and extraction with
methylene chloride (500 mL) yields
(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol
(Compound Xa) in solution. Addition of triethylamine (16.9 g,
0.1670 moles) and dichloroacetyl chloride (24.6 g, 0.1670 moles) at
20-30.degree. C. for 4-6 hours then removal of methylene chloride
by distillation and replacement by toluene (350 mL) and water (100
mL) precipitates the product. Filtration, washing with water (150
mL) and toluene (150 mL) then drying yields
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol).
Example 9
Purification of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0138]
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]--
1-propanol (Florfenicol) (45 g, 0.1256 moles) dissolves in water
(115 mL) and isopropanol (115 mL) at reflux. Cooling to
20-25.degree. C., filtration of the solids, washing with 1 to 1
water/isopropanol (50 mL) then drying gives pure
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol).
Example 10
Preparation and Purification of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0139]
(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)-
phenyl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl;
R.sub.2, R.sub.3 and R.sub.4 are methyl) (50.0 g, 0.1518 moles)
hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90
to 100.degree. C. over about 1 hour. Washing with methylene
chloride (200 mL), adjusting the pH to greater than 12 by addition
of sodium hydroxide and extraction with methylene chloride (300 mL)
yields
(1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol
(Compound Xa) in solution. Methanol (100 mL) replaces methylene
chloride which distills off. Addition of methyl dichloroacetate
(65.1 g, 0.4554 moles) and triethylamine (16.1 g, 0.1594 moles)
with agitation for 12-16 hours at 20-25.degree. C. then addition of
water (175 mL) and toluene (100 mL) precipitates the crude product.
Filtration, washing with water (100 mL) and toluene (174 mL) then
dissolution in water (115 mL) and isopropanol (115 mL) at reflux,
cooling to 20-25.degree. C., filtration of the solids, washing with
1 to 1 water/isopropanol (50 mL) then drying gives pure
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol).
Example 11
Preparation and Purification of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0140] Methylene chloride (450 mL) distills from a solution of
(4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phen-
yl]-1,3-oxazolidine (Compound IX: R.sub.1 is methylsulfonyl,
R.sub.2 and R.sub.3 are methyl and R.sub.4 is ethyl) (50.0 g,
0.1456 moles) after addition of water (300 mL) containing 20%
hydrochloric acid and heating to 90-100.degree. C. for 2-4 hours.
Adjusting the pH to greater than 12 by addition of sodium hydroxide
and extraction with methylene chloride (350 mL) yields a solution
of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol
(Compound Xa). Methanol (150 mL) replaces methylene chloride which
distills off. Addition of methyl dichloroacetate (52.0 g, 0.3640
moles) and triethylamine (11.0 g, 0.1092 moles) with agitation for
12-16 hours at 20-25.degree. C. then addition of water (150 mL) and
toluene (100 mL) precipitates the crude product. Filtration,
washing with water (75 mL) and toluene (125 mL) then dissolution in
water (50 mL) and isopropanol (100 mL) at reflux, cooling to
20-25.degree. C., filtration of the solids, washing with 1 to 1
water/isopropanol (50 mL) then drying gives pure
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1--
propanol (Florfenicol).
Example 12
Preparation of
(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfony-
l)phenyl]-1,3-oxazolidine (Compound XIIa)
[0141]
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propa-
noate (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.degree. C. to quantitatively yield
(1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol
(Compound VII: R.sub.1 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.degree. C. for 12-18 hours yields
(4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxa-
zolidine (Compound VIII: R.sub.1 is methylsulfonyl and R.sub.2 and
R.sub.3 are methyl). Addition of potassium carbonate (19.0 g,
0.1914 moles) and dichloroacetyl chloride (56.4 g, 0.3828 moles) at
20-25.degree. 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-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfony-
l)phenyl]-1,3-oxazolidine (Compound XIIa).
Example 13
Preparation of
(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl-
)phenyl]-1,3-oxazolidine (Compound XIIIa)
[0142]
(4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methyl-
sulfonyl)phenyl]-1,3-oxazolidine (Compound XIIa) (81 g, 0.2050
moles) in methylene chloride (450 ml) reacts with
N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent)
(73.2 g, 0.328 moles) at 95-105.degree. C. for 2-4 hours. Cooling
to 20-25.degree. C., quenching with 25% aqueous sodium hydroxide
and water (2000 mL) and separation of the methylene chloride layer
gives a solution of
(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfo-
nyl)phenyl]-1,3-oxazolidine (Compound XIIIa) for use as an
intermediate for the next step in the process.
Example 14
Preparation of
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol)
[0143]
(4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methyls-
ulfonyl)phenyl]-1,3-oxazolidine (Compound XIIIa) (60.5 g, 0.1519
moles) selectively hydrolyses in methylene chloride (300 mL) and
water (100 mL) containing p-toluene sulfonic acid at 60.degree. C.
over several hours. Removal of the methylene chloride by
distillation and cooling to 20-25.degree. C. precipitates the
product. Filtration, washing with water (100 mL) and toluene (100
mL) then drying yields
(1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propa-
nol (Florfenicol).
* * * * *