U.S. patent application number 09/746060 was filed with the patent office on 2001-07-05 for process for preparing azacycloalkanoylaminothiazoles.
Invention is credited to Chen, Bang-Chi, Kim, Kyoung S., Kimball, S. David, Misra, Raj N., Salvati, Mark E., Sundeen, Joseph E., Xiao, Hai-Yun, Zhao, Rulin.
Application Number | 20010006976 09/746060 |
Document ID | / |
Family ID | 27087817 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010006976 |
Kind Code |
A1 |
Chen, Bang-Chi ; et
al. |
July 5, 2001 |
Process for preparing azacycloalkanoylaminothiazoles
Abstract
The present invention relates to new, efficient processes for
the preparation of
5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds
of formula I 1 or a pharmaceutically acceptable salt thereof,
wherein: R is alkyl, aryl or heteroaryl; R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are each independently hydrogen, alkyl, aryl or
heteroaryl; R.sup.6 and R.sup.7 are each independently hydrogen,
alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; R.sup.8 is
hydrogen, alkyl, aryl, heteroaryl, CONR.sup.9R.sup.10, COR.sup.11
or COOR.sup.12; R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each
independently hydrogen, alkyl or aryl; m equals 0 to 5; and n
equals 0 to 5, which are novel, potent inhibitors of cyclin
dependent kinases (cdks). The present invention further concerns
new key intermediate compounds, a quaternary ammonium salt of
formula III' and a 2-oxazolylalkyl derivative of formula IX.
Inventors: |
Chen, Bang-Chi; (Plainsboro,
NJ) ; Kim, Kyoung S.; (North Brunswick, NJ) ;
Kimball, S. David; (East Windsor, NJ) ; Misra, Raj
N.; (Hopewell, NJ) ; Salvati, Mark E.;
(Lawrenceville, NJ) ; Sundeen, Joseph E.;
(Yardley, PA) ; Xiao, Hai-Yun; (Princeton, NJ)
; Zhao, Rulin; (Pennington, NJ) |
Correspondence
Address: |
MARLA J MATHIAS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27087817 |
Appl. No.: |
09/746060 |
Filed: |
December 22, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09746060 |
Dec 22, 2000 |
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09616627 |
Jul 26, 2000 |
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09616627 |
Jul 26, 2000 |
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09464511 |
Dec 15, 1999 |
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09464511 |
Dec 15, 1999 |
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09176239 |
Oct 21, 1998 |
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6040321 |
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Current U.S.
Class: |
514/369 ;
546/209; 548/167 |
Current CPC
Class: |
C07D 417/14 20130101;
A61K 31/427 20130101; A61P 35/00 20180101; C07D 417/12 20130101;
C07D 231/12 20130101; A61K 31/454 20130101; C07D 249/08 20130101;
C07D 233/56 20130101 |
Class at
Publication: |
514/369 ;
548/167; 546/209 |
International
Class: |
C07D 277/62; C07D
401/00; C07D 405/00; C07D 409/00; C07D 411/00; C07D 413/00; A61K
031/425 |
Claims
What is claimed is:
1. A process for the preparation of a compound having the formula I
14or a pharmaceutically acceptable salt thereof, wherein: R is
alkyl, aryl or heteroaryl; R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 are each independently hydrogen, alkyl, aryl or heteroaryl;
R.sup.6 and R.sup.7 are each independently hydrogen, alkyl, aryl,
heteroaryl, halogen, hydroxy or alkoxy; R.sup.8 is hydrogen, alkyl,
aryl, heteroaryl, CONR.sup.9R.sup.10, COR.sup.11 or COOR.sup.12;
R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each independently
hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to 5;
which comprises the steps of: (a) reacting an .alpha.-substituted
ketone having the formula II 15wherein: R and R.sup.1 are as
described hereinabove; and L is halogen or sulfonate; with a cyclic
alkylenetetramine in a suitable solvent or solvent mixture to form
a quaternary ammonium salt; (b) reacting the quaternary ammonium
salt with an acid in a suitable solvent or solvent mixture to form
an .alpha.-amino ketone; (c) reacting the .alpha.-amino ketone with
an .alpha.-substituted acyl derivative having the formula V
16wherein: R.sup.2, R.sup.3 and L are as described hereinabove; and
X is hydroxy, halogen or acyloxy; in the presence of a base in a
suitable solvent or solvent mixture to form an amide; or,
alternatively, reacting the .alpha.-amino ketone with an
.alpha.-substituted acid in the presence of a coupling reagent to
form the corresponding amide; (d) reacting the amide with a
dehydrating reagent in a suitable solvent or solvent mixture to
give a 2-oxazolylalkyl derivative; (e) reacting the 2-oxazolylalkyl
derivative with a sulfur-containing reagent in a suitable solvent
or solvent mixture to give a 2-oxazolylalkyl sulfide compound; (f)
reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole
compound in the presence of a base in a suitable solvent or solvent
mixture to give a 5-(2-oxazolylmethylthio)-2-aminothiazole
compound; (g) reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole
with an azacycloalkanoic acid derivative having the formula XII
17wherein: R.sup.6, R.sup.7 and X are as described hereinabove; P
is a nitrogen-protecting group; m equals 0 to 5; and n equals O to
5; in the presence of a coupling reagent in a suitable solvent or
solvent mixture to form a thiazolyl amide; and (h) reacting the
thiazolyl amide with a deprotecting reagent in a suitable solvent
or solvent mixture to form the compound of formula I.
2. The process as recited in claim 1, wherein the
.alpha.-substituted ketone in step (a) is an .alpha.-halo
ketone.
3. The process as recited in claim 2, wherein the .alpha.-halo
ketone is an .alpha.-halo aliphatic ketone or an .alpha.-halo
aromatic ketone.
4. The process as recited in claim 3, wherein the .alpha.-halo
ketone is an .alpha.-halo pinacolone.
5. The process as recited in claim 4, wherein the .alpha.-halo
pinacolone is .alpha.-bromo pinacolone.
6. The process as recited in claim 1, wherein the solvent in step
(a) is a hydrocarbon, an ether, an amide, a ketone or a mixture
thereof.
7. The process as recited in claim 6, wherein the solvent is the
ketone and the ketone is acetone.
8. The process as recited in claim 1, wherein the cyclic
alkylenetetramine in step (a) is hexamethylenetetramine.
9. The process as recited in claim 1, wherein the acid in step (b)
is HCl, HBr, HI, H.sub.2SO.sub.4 or H.sub.3PO.sub.4.
10. The process as recited in claim 9, wherein the acid is HCl.
11. The process as recited in claim 1, wherein the solvent in step
(b) is a hydrocarbon, an ether, an alcohol or a mixture
thereof.
12. The process as recited in claim 11, wherein the solvent is the
alcohol and the alcohol is ethanol.
13. The process as recited in claim 1, further comprising isolating
the .alpha.-amino ketone product as the salt or free base form
before performing step (c).
14. The process as recited in claim 1, wherein the
.alpha.-substituted acyl derivative in step (c) is an .alpha.-halo
acyl halide.
15. The process as recited in claim 14, wherein the .alpha.-halo
acyl halide is .alpha.-chloroacetyl chloride.
16. The process as recited in claim 1, wherein the base in step (c)
is an aromatic organic amine or an aliphatic organic amine.
17. The process as recited in claim 16, wherein the base is the
aliphatic organic amine and the aliphatic organic amine is
triethylamine.
18. The process as recited in claim 1, wherein the
.alpha.-substituted acid in step (c) is an .alpha.-halo acid halide
and the coupling reagent is water-soluble.
19. The process as recited in claim 18, wherein the coupling
reagent is a carbodiimide, a haloformate or a thionyl halide.
20. The process as recited in claim 1, wherein the dehydrating
reagent in step (d) is an acid, an acid anhydride or a base.
21. The process as recited in claim 1, wherein the dehydrating
reagent in step (d) is concentrated sulfuric acid, polyphosphoric
acid, trichlorophosphorus oxide, tribromophosphorus oxide or
(methoxycarbonylsulfamoyl)triethylammonium hydroxide.
22. The process as recited in claim 21, wherein the dehydrating
reagent is (methoxycarbonylsulfamoyl)triethylammonium
hydroxide.
23. The process as recited in claim 1, wherein the solvent in step
(d) is tetrahydrofuran.
24. The process as recited in claim 1, wherein the dehydrating
reagent in step (d) is (methoxycarbonylsulfamoyl)triethylammonium
hydroxide and the solvent is tetrahydrofuran.
25. The process as recited in claim 1, wherein the
sulfur-containing reagent in step (e) is an N-substituted thiourea,
an unsubstituted thiourea, a thio acid or a salt thereof, or a
xanthic acid or a salt thereof.
26. The process as recited in claim 25, wherein the
sulfur-containing reagent is thiourea, thioacetic acid or the salt
thereof, or ethylxanthic acid potassium salt.
27. The process as recited in claim 1, wherein the
5-halo-2-aminothiazole compound in step (f) is
5-bromo-2-aminothiazole.
28. The process as recited in claim 1, wherein the base in step (f)
is a metal hydroxide, a metal alkoxide, a metal carbonate or an
aqueous amine.
29. The process as recited in claim 28, wherein the base is the
metal hydroxide and the metal hydroxide is sodium hydroxide.
30. The process as recited in claim 1, wherein the solvent in step
(f) is a hydrocarbon, a halogenated hydrocarbon, an ether, an
ester, an amide, an alcohol or a mixture thereof.
31. The process as recited in claim 30, wherein the solvent is the
halogenated hydrocarbon and the halogenated hydrocarbon is
dichloromethane.
32. The process as recited in claim 1, wherein the
nitrogen-protecting group in step (g) is Boc or Cbz.
33. The process as recited in claim 1, wherein the coupling reagent
in step (g) is a carbodiimide, a haloformate or a thionyl
halide.
34. The process as recited in claim 33, wherein the coupling
reagent is the carbodiimide and the carbodiimide is an
alkylcarbodiimide.
35. A process for the preparation of a compound having the formula
III' 18or a salt thereof, wherein: R is alkyl; R.sup.1 is hydrogen,
alkyl, aryl or heteroaryl; and L is halogen or a sulfonate; which
comprises reacting an .alpha.-substituted ketone having the formula
II 19wherein: R, R.sup.1 and L are as described hereinabove; with a
cyclic alkylenetetramine in a suitable solvent or solvent mixture
to form the compound of formula III'.
36. The process as recited in claim 35, wherein R is t-butyl.
37. The process as recited in claim 35, wherein the cyclic
alkylenetetramine is hexanethylenetetramine.
38. A process for the preparation of a compound having the formula
IX 20or a salt thereof, wherein: R is alkyl, aryl or heteroaryl;
R.sup.1, R.sup.2 and R.sup.3 are each independently hydrogen,
alkyl, aryl or heteroaryl; Y is O, S, NH, N-alkyl, N-aryl or
N-acyl; and Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl,
S-aryl, NH.sub.2, N-alkyl, N-aryl or N-acyl; which comprises
reacting a 2-oxazolylalkyl derivative having the formula VII
21wherein: R, R.sup.1, R.sup.2 and R.sup.3 are as described
hereinabove; and L is halogen or sulfonate; with a
sulfur-containing reagent in a suitable solvent or a solvent
mixture to form the compound of formula IX.
39. The process as recited in claim 38, wherein the
sulfur-containing reagent is an N-substituted thiourea, an
unsubstituted thiourea, a thio acid or a salt thereof, or a xanthic
acid or a salt thereof.
40. The process as recited in claim 39, wherein the
sulfur-containing reagent is thiourea, thioacetic acid or the salt
thereof, or ethylxanthic acid potassium salt.
41. The process as recited in claim 38, wherein the solvent is a
hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an
amide, an alcohol or a mixture thereof.
42. The process as recited in claim 41, wherein the solvent is the
alcohol and the alcohol is methanol or ethanol.
43. A compound having the formula III' 22or a salt thereof,
wherein: R is alkyl; R.sup.1 is hydrogen, alkyl, aryl or
heteroaryl; and L is halogen or a sulfonate.
44. The compound as recited in claim 43, wherein R is t-butyl.
45. The compound as recited in claim 44, wherein R.sup.1 is
hydrogen.
46. The compound as recited in claim 45, wherein L is halogen.
47. The compound as recited in claim 46,
.alpha.-hexamethylenetetramino-pi- nacolone bromide.
48. A compound having the formula IX 23or a salt thereof, wherein:
R is alkyl, aryl or heteroaryl; R.sup.1, R.sup.2 and R.sup.3 are
each independently hydrogen, alkyl, aryl or heteroaryl; Y is O, S,
NH, N-alkyl, N-aryl or N-acyl; and Z is hydrogen, alkyl, aryl,
O-alkyl, O-aryl, S-alkyl, S-aryl, NH.sub.2, N-alkyl, N-aryl or
N-acyl.
49. The compound as recited in claim 48, wherein R is t-butyl; Y is
NH, N-alkyl, N-aryl or N-acyl and Z is NH.sub.2, N-alkyl, N-aryl or
N-acyl.
50. The compound as recited in claim 49, wherein the salt is
hydrochloride.
51. The compound as recited in claim 50,
5-(t-butyl)-2-oxazolylmethyl thiouronium hydrochloride.
Description
CROSS-REFERENCE TO RELATED U.S. APPLICATIONS
[0001] This application is a continuation-in-part of (1) patent
application Ser. No. 09/616,627, filed on Jul. 26, 2000 and (2)
patent application Ser. No. 09/616,629, filed on Jul. 26, 2000,
which are continuation-in-part applications of patent application
Ser. No. 09/464,511, filed Dec. 15, 1999.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
REFERENCE TO A "Microfiche Appendix"
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] The present invention concerns new processes for the
preparation of
5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and
analogs, inhibitors of cyclin dependent kinases.
[0006] 2. Description of the Related Art
[0007] The 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole
compounds of formula I 2
[0008] or a pharmaceutically acceptable salt thereof, wherein:
[0009] R is alkyl, aryl or heteroaryl;
[0010] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each
independently hydrogen, alkyl, aryl or heteroaryl;
[0011] R.sup.6 and R.sup.7 are each independently hydrogen, alkyl,
aryl, heteroaryl, halogen, hydroxy or alkoxy;
[0012] R.sup.8 is hydrogen, alkyl, aryl, heteroaryl,
CONR.sup.9R.sup.10, COR.sup.11 or COOR.sup.12;
[0013] R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each
independently hydrogen, alkyl or aryl;
[0014] m equals 0 to 5; and
[0015] n equals 0 to 5,
[0016] are novel, potent inhibitors of cyclin dependent kinases
(cdks). They are useful in the therapy of proliferative diseases,
for example, cancer, inflammation, autoimmune diseases such as
arthritis, viral diseases, fungal diseases, chemotherapy-induced
alopecia, neurodegenerative disorders such as Alzheimer's disease
and cardiovascular disease. More specifically, the compounds of
formula I are useful in the treatment of a variety of cancers such
as bladder, breast, colon, kidney, liver and lung cancers.
[0017] WO 9924416 and corresponding U.S. Pat. No. 6,040,321
describe the preparation of
5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the
synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkan-
oylaminothiazoles of formula I, by reacting
5-acetylthio-2-acetylaminothia- zole with a base followed by
trapping the thiolate with a 2-oxazolylalkyl halide. Hydrolysis of
the resulting 5-(2-oxazolylalkylthio)-2-acetylamino- thiazole
compounds afforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key
intermediates. The requisite 2-oxazolylalkyl halides were prepared
by (i) reaction of .beta.-hydroxy amines with .alpha.-chloroacyl
chlorides followed by oxidation of the resulting
.beta.-hydroxy-.alpha. -chloroamides and subsequent oxazole ring
formation (K. S. Kim et al., WO 9924416, May 20, 1999) or (ii)
reaction of .alpha.-diazo ketones with .alpha.-chloronitriles (K.
S. Kim et al, WO 9924416, May 20, 1999; T. Ibata et al., Bull.
Chem. Soc. Japan 1979, 52, 3597). Although a variety of
5-(2-oxazolylalkylthio)-2-aminothiazoles can be prepared by this
method, this process is not amenable to large scale synthesis due
to the commercial availability of the starting
5-acetylthio-2-acetylaminothiazol- e, the use of hazardous
.alpha.-diazo ketones and expensive chromatographic separation of
products.
[0018] Reaction of .alpha.-halo ketones with azide to give
.alpha.-azido ketones has been previously reported in the
literature (A. Hassner et al., Angew Chem. Int. Ed. Engl. 1986, 25,
478; M. G. Nair et al., J. Med. Chem. 1980, 23, 899; H.-J. Ha et
al., Synth. Commun. 1994, 24, 2557). Reaction of
.alpha.-sulfonyloxy ketones with azide to give .alpha.-azido
ketones has also been previously reported (T. Patonay et al., J.
Org. Chem. 1994, 59, 2902; G. A. Revelli et al, Synth. Commun.
1993, 23, 1111).
[0019] Reduction of .alpha.-azido ketones to .alpha.-amino ketones
has been described in the literature (H.-J. Ha et al., Synth.
Commun. 1994, 24, 2557; J. P. Sanchez et al., J. Heterocycl. Chem.
1988, 25, 469; S. K. Boyer et al., J. Org. Chem. 1985, 50, 3408).
Reaction of .alpha.-amino ketones with .alpha.-halo acyl halides to
give the corresponding amides has further been described (G. T.
Newbold et al., J. Chem. Soc. 1948, 1855; G. T. Newbold et al., J.
Chem. Soc. 1950, 909).
[0020] Reaction of alkylthiouronium salts with alkyl halides to
give sulfides has been previously reported (H. Chen et al., Synth.
Commun. 1990, 20, 3313). Reaction of alkylthiols with
5-bromo-2-aminothiazole to give 5-alkylthio-2-aminothiazoles has
been reported (J. B. Dickey et al., J. Org. Chem. 1959, 24,
187).
BRIEF SUMMARY OF THE INVENTION
[0021] This invention concerns new efficient processes for the
preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles. The
processes involve new strategies for the preparation of
2-oxazolylalkyl halides and
5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method
of making new key intermediate quaternary ammonium salts and
2-oxazolylalkyl sulfide derivatives. This invention further relates
to processes for the preparation of
5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and
analogs, inhibitors of cyclin dependent kinases.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Not Applicable
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention relates to new, more efficient
processes for the preparation of
5-(2-oxazolylalkylthio)-2-aminothiazoles with application to the
synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoy-
laminothiazoles and analogs, inhibitors of cyclin dependent
kinases. The process generally involves reaction of .alpha.-halo
ketones II with an azide to give .alpha.-azido ketones III.
Reduction of III with a reducing reagent gives .alpha.-amino
ketones IV. From a practical standpoint, safety concerns make this
reaction through the azide economically unfeasible.
[0024] Alternatively and more advantageously, the .alpha.-amino
ketones IV are prepared by reaction of .alpha.-halo ketones II with
a cyclic alkylenetetramine such as hexamethylenetetramine and the
like, followed by hydrolysis of the resulting, new quaternary
ammonium salt III'. This reaction provides excellent yields of the
desired intermediate compound IV, above 90%, yet in a safer
manner.
[0025] Thereafter, reacting the .alpha.-amino ketones IV with an
.alpha.-halo acyl halide V in the presence of a base or,
alternatively, coupling the .alpha.-amino ketones IV with an
.alpha.-halo acid, produces the corresponding amides VI. Then, ring
closure of VI with a dehydrating reagent affords 2-oxazolylalkyl
halides VII. When a conventional dehydrating reagent such as
trihalophosphorus oxide like POCl.sub.3 is used, product isolation
is difficult due to the formation of large amounts of hydrochloric
and phosphoric acids. Thus, the process of the present invention
preferably utilizes the Burgess' reagent which produces excellent
yields and permits easy, safe product isolation from water.
[0026] Subsequent treatment of 2-oxazolylalkyl halides VII with
sulfur-containing reagent VIII or VIII' affords new key
intermediate compounds, 2-oxazolylalkyl sulfides IX. Coupling of IX
with 5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2
-aminothiazoles XI. Coupling of XI with an azacycloalkanoic acid
derivative XII affords thiazolyl amides XIII, which may be
deprotected (in the case where P is a protecting group, e.g., Boc)
to give 5-(2-oxazolylalkylthio)-2-azacycloal- kanoylaminothiazoles
I, where R.sup.7 is hydrogen, inhibitors of cyclin dependent
kinases.
[0027] The above-described reactions are illustrated in the below
Scheme 1. 3
[0028] In formulas I-XIII of Scheme 1, the following terms
apply:
[0029] R is alkyl, aryl or heteroaryl;
[0030] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each
independently hydrogen, alkyl, aryl or heteroaryl;
[0031] R.sup.6 and R.sup.7 are each independently hydrogen, alkyl,
aryl, heteroaryl, halogen, hydroxy or alkoxy;
[0032] R.sup.8 is hydrogen, alkyl, aryl, heteroaryl,
CONR.sup.9R.sup.10, COR.sup.11 or COOR.sup.12;
[0033] R.sup.9, R.sup.10, R.sup.11 and R.sup.12 are each
independently hydrogen, alkyl or aryl;
[0034] L is halogen or sulfonate (RSO.sub.2O--,
CF.sub.3SO.sub.2O--, etc.);
[0035] M is hydrogen, Li, Na, K, Cs or quaternary ammonium
(R.sub.4N);
[0036] X is hydroxy, halogen or acyloxy (RCOO--, ROCOO--,
etc.);
[0037] Y is O, S, NH, N-alkyl, N-aryl or N-acyl;
[0038] Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl,
S-aryl, NH.sub.2, N-alkyl, N-aryl or N-acyl;
[0039] P is a nitrogen-protecting group (Boc, Cbz, R.sub.3Si,
etc.);
[0040] m equals 0 to 5; and
[0041] n equals 0 to 5.
[0042] Listed below are definitions of various terms used to
describe the compounds involved in the processes of the present
invention. These definitions apply to the terms as they are used
throughout the specification (unless specifically indicated
otherwise) either individually or as part of a larger group. It
should be noted that any heteroatom with unsatisfied valences is
assumed to have the hydrogen atom to satisfy the valences.
[0043] The term "alkyl" or "alk" (i.e., derivative forms of alkyl)
refers to optionally substituted straight chain, branched or cyclic
monovalent alkane (saturated hydrocarbon) derived radicals
containing from 1 to 12 carbon atoms. When substituted, alkyl
groups may be substituted with up to four substituent groups at any
available point of attachment. Examples of alkyl groups include,
but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,
t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl and the like. The alkyl can be optionally
substituted with one or more halogens or alkyl groups such as, for
example, trifluoromethyl, 4,4-dimethylpentyl,
2,2,4-trimethylpentyl, etc.
[0044] The term "aryl" or derivative forms thereof refers to
monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted
phenyl and the like, as well as groups which are fused, e.g.,
napthyl, phenanthrenyl and the like, containing from 6 to 30 carbon
atoms. An aryl group can thus contain at least one ring having 6
atoms, with up to five such rings being present, containing up to
22 or 30 atoms therein, depending upon optionally alternating
(resonating) double bonds between carbon atoms or suitable
heteroatoms. Examples of aryl groups include, but are not limited
to, phenyl, naphthyl, anthryl, biphenyl and the like.
[0045] The term "acyl" refers to the radical RCO--, taken alone or
in combination, for example, with oxygen, nitrogen, sulfur, etc.
The term "halogen" or "halo" refers to chlorine, bromine, fluorine
or iodine, with bromine being the preferred halogen.
[0046] The term "heteroaryl" refers to a monocyclic aromatic
hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic
group having 8 to 10 atoms, containing at least one heteroatom, O,
S or N, in which a carbon or nitrogen atom is the point of
attachment, and in which one or two additional carbon atoms is
optionally replaced by a heteroatom selected from O or S, and in
which from 1 to 3 additional carbon atoms are optionally replaced
by nitrogen heteroatoms, said heteroaryl group being optionally
substituted as described herein. Exemplary heteroaryl groups
include, but are not limited to, thienyl, furyl, pyrrolyl,
pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl,
oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
pyrazinyl, pyridazinyl, pyrimidinal, triazinylazepinyl, indolyl,
isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, etc.
The heteroaryl groups can be optionally substituted by one or more
groups which include, but are not limited to, halogen, alkyl,
alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl,
trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O).sub.m
(where m=0, 1 or 2), thiol and the like.
[0047] When a functional group is termed "protected," this means
that the group is in modified form to preclude undesired side
reactions at the protected site. Suitable protecting groups for the
compounds involved in the present processes will be recognized from
the specification taking into account the level of skill in the
art, and with reference to standard textbooks such as T. W. Greene
et al., Protective Groups in Organic Synthesis, Wiley, N.Y.
(1991).
[0048] The term "pharmaceutically acceptable salt" refers to those
salts of the biologically active compounds which do not
significantly or adversely affect the pharmaceutical properties of
the compounds such as, for example, toxicity, efficacy, etc. and
include those salts which are conventionally employed in the
pharmaceutical industry. Suitable examples of salts include, but
are not limited to, those formed with inorganic or organic acids
such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Also
included, particularly for the intermediate compounds of the
invention, are salts which are unsuitable for pharmaceutical
utility but which can be employed otherwise, for example, for
isolation or purification of free active compounds or their
pharmaceutically acceptable salts.
[0049] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The definition of the compounds employed in the
processes of the invention embraces all possible stereoisomers and
their mixtures. The definition further embraces the racemic forms
and the isolated optical isomers having the specified activity. The
racemic forms can be resolved by physical methods such as, for
example, fractional crystallization, separation or crystallization
of diastereomeric derivatives or separation by chiral column
chromatography. The individual optical isomers can be obtained from
the racemates by conventional methods such as, for example, salt
formation with an optically active acid followed by
crystallization.
[0050] It should be understood that solvates (e.g., hydrates) of
the compounds of formula I and the intermediate compounds are also
within the scope of the present invention. Methods of salvation are
generally known in the art. Therefore, the compounds useful in the
processes of this invention may be in the free or hydrate form.
[0051] As set forth in Scheme 1, the processes for the preparation
of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and
analogs involve the following transformations:
[0052] (a) reacting an .alpha.-substituted ketone II such as, for
example, an .alpha.-halo ketone, with an azide in a suitable
solvent or solvent mixtures to give an .alpha.-azido ketone III;
or, more desirably, (a') reacting an .alpha.-substituted ketone II
like the .alpha.-halo ketone with a cyclic alkylenetetramine such
as, for example, hexamethylenetetramine in a suitable solvent or
solvent mixtures to give a new quaternary ammonium salt III'.
[0053] The .alpha.-halo ketone includes .alpha.-halo aliphatic and
.alpha.-halo aromatic ketones. The preferred .alpha.-halo ketones
are .alpha.-halo pinacolones with .alpha.-bromo pinacolone most
preferred. A sulfonate, for example, RSO.sub.2O-- (where R is
alkyl, aryl or heteroaryl), CF.sub.3SO.sub.2O-- and the like, may
be substituted for the halogen in the .alpha.-position. The azides
include both metal azides and quaternary ammonium azides. The metal
azides are preferred with sodium azide most preferred. Suitable
solvent(s) include solvents such as hydrocarbons, ethers, amides,
for example, dimethylformamide, ketones, etc., or mixtures thereof,
with ketones such as acetone preferred for both reactions (a) and
(a').
[0054] b) reacting the .alpha.-azido ketone III obtained in step
(a) with a reducing reagent in a suitable solvent or solvent
mixtures to give an .alpha.-amino ketone IV, or, more desirably,
(b') reacting the quaternary ammonium salt III' obtained in step
(a') with an acid in a suitable solvent or solvent mixtures to give
an .alpha.-amino ketone IV.
[0055] The reducing reagent in reaction (b) includes hydrogen in
the presence of a transition metal catalyst such as palladium,
trialkyl or triarylphosphines like triphenylphosphine. Hydrogen in
the presence of a transition metal catalyst is preferred with
hydrogen and palladium over activated carbon most preferred.
Suitable solvent(s) in reaction (b) include solvents such as
hydrocarbons, ethers, alcohols and the like, or mixtures thereof,
with alcohol such as methanol preferred. Alternatively, the
reduction reaction can be carried out in the presence of an acidic
medium such as, for example, hydrochloric acid in ethanol to give
.alpha.-amino ketone acid salt which can be isolated as the acid
salt or free amine forms.
[0056] The acid in reaction (b') includes, but is not limited to,
protic acids such as HCl, HBr, H[, H.sub.2SO.sub.4,
H.sub.3PO.sub.4, etc., with HCl preferred. Suitable solvent(s) in
reaction (b') include solvents such as hydrocarbons, ethers,
alcohols and the like, or mixtures thereof, with alcohol such as
ethanol preferred. The .alpha.-amino ketone product may be isolated
as the salt or free base forms.
[0057] (c) reacting (acylating) the .alpha.-amino ketone IV or its
acid salt obtained in step (b) or (b') with an .alpha.-substituted
acyl derivative V such as, for example, an .alpha.-halo acyl
halide, in the presence of a base and in a suitable solvent or
solvent mixtures to give an amide VI.
[0058] The .alpha.-halo acyl halide V includes .alpha.-alkyl or
aryl substituted or unsubstituted .alpha.-halo acyl halide with the
latter preferred. The most preferred .alpha.-halo acyl halide is
.alpha.-chloroacetyl chloride. The base used in the reaction
includes, but is not limited to, aromatic and aliphatic organic
amines with the latter preferred. The most preferred base is
triethylamine. Suitable solvent(s) include aprotic solvents such as
hydrocarbons, halogenated hydrocarbons, ethers, esters and the
like, or mixtures thereof, with halogenated hydrocarbons such as
dichloromethane preferred. Alternatively, the reaction can be
carried out using an .alpha.-substituted acid instead of the
.alpha.-substituted acyl derivative and then employing a coupling
reagent such as a water-soluble diimide like carbodiimide,
haloformate, thionyl halide, etc. In either reaction, a sulfonate,
for example, RSO.sub.2O-- (where R is an alkyl, aryl or
heteroaryl), CF.sub.3SO.sub.2O-- and the like, may be substituted
for the halogen in the .alpha.-position of the .alpha.-halo acyl
halide or the .alpha.-halo acid reactants which are
illustrated.
[0059] (d) reacting the amide VI obtained in step (c) with a
dehydrating reagent in a suitable solvent or solvent mixtures to
give the cyclized 2-oxazolylalkyl derivative VII such as, for
example, the 2-oxazolylalkyl halide.
[0060] Advantageously, the reaction is carried out using
(methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess'
reagent) as the dehydrating reagent. Suitable solvent(s) include
hydrocarbons, halogenated hydrocarbons, ethers and the like, or
mixtures thereof. Most preferred is the use of the Burgess' reagent
in tetrahydrofuran. Suitable dehydrating reagents also include, but
are not limited to, other bases, acids, acid anhydrides and the
like, such as, e.g., concentrated sulfuric acid, polyphosphoric
acid, etc. Although less conveniently, the dehydrating reagent, for
instance, can be trihalophosphorus oxide such as tribromophosphorus
oxide or trichlorophosphorus oxide, alone or with a solvent like
toluene.
[0061] (e) reacting the 2-oxazolylalkyl derivative VII obtained in
step (d) with a sulfur-containing reagent VIII or VIII' in a
suitable solvent or solvent mixtures to give 2-oxazolylalkyl
sulfide IX, a new key intermediate compound.
[0062] The sulfur-containing reagent includes N-substituted or
unsubstituted thioureas, thio acids or salts such as thioacetic
acid or its salt, xanthic acids or salts such as ethylxanthic acid
potassium salt. Unsubstituted thiourea is preferred. Suitable
solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers,
esters, amides, alcohols and the like, or mixtures thereof, with
alcohol such as methanol or ethanol preferred.
[0063] (f) reacting the 2-oxazolylalkyl sulfide IX obtained in step
(e) with a 5-halo-2-aminothiazole X in the presence of a base and
in a suitable solvent or solvent mixtures to give
5-(2-oxazolylalkylthio)-2-am- inothiazole XI.
[0064] The 5-halo-2-aminothiazole includes 4,N-substituted or
unsubstituted 5-halo-2-aminothiazoles with 5-bromo-2-aminothiazole
preferred. A suitable base includes, but is not limited to, metal
hydroxide, metal alkoxides, metal carbonates and aqueous amines
such as ammonium hydroxide. Sodium hydroxide is preferred. Suitable
solvent(s) include solvents such as hydrocarbons, halogenated
hydrocarbons, ethers, esters, amides, alcohols and the like, or
mixtures thereof, with halogenated hydrocarbons such as
dichloromethane preferred.
[0065] (g) reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XI
obtained in step (f) with an azacycloalkanoic acid derivative XII
in the presence of a coupling reagent in a suitable solvent or
solvent mixtures to give thiazolyl amide XIII.
[0066] The azacycloalkanoic acid derivative includes N-protected
derivatives, for example, N-protected isonipecotic acid or
N-protected nipecotic acid. The preferred nitrogen-protecting
groups are Boc, Cbz, silicon derivatives and the like with Boc
being the most preferred. The coupling reagent includes, but is not
limited to, water-soluble carbodiimides, haloformates and the like,
with carbodiimides such as alkylcarbodiimides being preferred.
Suitable solvent(s) include solvents such as hydrocarbons,
halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures
thereof, with halogenated hydrocarbons such as dichloromethane
preferred.
[0067] (h) reacting the thiazolyl amide XIII obtained in step (g)
with a deprotecting reagent in a suitable solvent or solvent
mixtures to give a desired
5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole I (where
R.sup.7 is hydrogen).
[0068] The choice of the deprotecting reagent is based on the
nature of the protecting group (P). For the Boc protecting group,
the preferred deprotecting reagent is an acid such as hydrochloric
acid or trifluoroacetic acid and suitable solvent(s) for such
deprotecting reaction include solvents such as hydrocarbons,
halogenated hydrocarbons, ethers, esters, amides and the like, or
mixtures thereof, with halogenated hydrocarbons such as
dichloromethane preferred.
[0069] The starting compounds of Scheme 1 are commercially
available or may be prepared by methods known to one of ordinary
skill in the art.
[0070] To further illustrate Scheme 1, a process to make
5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoylaminothiazoles
and analogs thereof, for example, starts with reaction of
.alpha.-bromo pinacolone II (R=Bu-t, R.sup.1=H, L=Br) with sodium
azide to give an .alpha.-azido pinacolone III (R=Bu-t, R.sup.1=H).
Reduction of .alpha.-azido pinacolone III (R=Bu-t, R.sup.1=H) with
a reducing reagent gives .alpha.-amino pinacolone IV (R=Bu-t,
R.sup.1=H). Alternatively and more desirably, the .alpha.-amino
pinacolone IV (R= Bu-t, R.sup.1=H) is prepared by reaction of
.alpha.-bromo pinacolone II (R=Bu-t, R.sup.1=H, L=Br) with
hexamethylenetetramine followed by hydrolysis of the resulting
quaternary ammonium salt III' (R=Bu-t, R.sup.1=H, L=Br). Coupling
of .alpha.-amino pinacolone IV (R= Bu-t, R.sup.1=H) with an
.alpha.-chloroacetyl chloride V (R.sup.2=R.sup.3=H, L=X=Cl)
produces amide VI (R=Bu-t, R.sup.1=R.sup.2=R.sup.3=H, L=Cl). Ring
closure of VI with a dehydrating reagent affords
5-t-butyl-2-oxazolylmethyl chloride VII (R=Bu-t,
R.sup.1=R.sup.2=R.sup.3=H, L= Cl). Treatment of VII with
sulfur-containing reagent VIII or VIII' such as thiourea affords
5-t-butyl-2-oxazolylalkyl sulfide IX (R=Bu-t,
R.sup.1=R.sup.2=R.sup.3=H, Y=NH, Z= NH.sub.2). Coupling of IX with
5-bromo-2-aminothiazole X (R.sup.4=R.sup.5=H, L=Br) gives
5-(5-t-butyl-2-oxazolylmethylthio)-2-amin- othiazole XI (R=Bu-t,
R=R.sup.2=R=R=R.sup.5=H). Coupling of XI with N-Boc
azacycloalkanoic acid XII (X=OH, R.sup.6=R.sup.7=H, m=0, n= 2,
P=Boc), affords thiazolyl amide XIII (R=Bu-t,
R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.s- up.5=R.sup.6=R.sup.7= H, m=0,
n=2, P=Boc), which after deprotection, gives rise to the desired
5-(5-t-butyl-2-oxazolylmethylthio)-2-azacycloalkanoyl-
aminothiazole I (R=Bu-t, R.sup.1=R.sup.2=R.sup.3=R.sup.4=
R.sup.5=R.sup.6=R.sup.7=R.sup.8=H, m=0, n=2), or an analog
thereof.
[0071] The present invention further includes two novel key
intermediate compounds of formulae III' and IX which have been
produced from the new processes to synthesize
5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminoth- iazoles of
formula I.
[0072] The following examples demonstrate certain aspects of the
present invention. However, it is to be understood that these
examples are for illustration only and do not purport to be wholly
definitive as to conditions and scope of this invention. It should
be appreciated that when typical reaction conditions (e.g.,
temperature, reaction times, etc.) have been given, the conditions
both above and below the specified ranges can also be used, though
generally less conveniently. The examples are conducted at room
temperature (about 23.degree. C. to about 28.degree. C.) and at
atmospheric pressure. All parts and percents referred to herein are
on a weight basis and all temperatures are expressed in degrees
centigrade unless otherwise specified.
[0073] A further understanding of the invention may be obtained
from the non-limiting examples which follow below.
EXAMPLE 1
A. Preparation of .alpha.-Azido-pinacolone
[0074] 4
[0075] .alpha.-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was
combined in 1.785 L of acetone with sodium azide (93.9 g, 1.4444
mol, 1.3 eq). The reaction was stirred at room temperature for 27.5
hours. The resulting slurry was filtered and washed with acetone
(3.times. 150 mL). The filtrate was concentrated in vacuo to
provide 154.3 g (98.4%) of the title compound. HPLC 83.85% at 2.57
minutes (Phenomenex Inc., Torrance, Calif., 5 .mu.m C18 column
4.6.times.50 mm, 10-90% aqueous methanol over 4 minutes containing
0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
EXAMPLE 2
A' Preparation of .alpha.-Hexamethylenetetramino-pinacolone
Bromide
[0076] 5
[0077] .alpha.-Bromo-pinacolone (179 g, 1 mol, 1 eq) was combined
in 2 L of acetone with hexamethylenetetramine (154.21 g, 1.1 mol,
1.1 eq) and the reaction stirred under N.sub.2 at room temperature
for 26 hours. The resulting slurry was filtered, the filter cake
was washed with ether (3.times.50 mL) and dried in vacuo at
50.degree. C. overnight to provide 330 g (100%) of the title
compound containing 7% hexamethylenetetramine. HPLC R.T.=0.17 min
(Phenomenex Inc., 5 .mu.m C18 column 4.6.times.50 mm, 10-90%
aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4
mL/min, monitoring at 220 nm).
EXAMPLE 3
B. Preparation of .alpha.-Amino-pinacolone Hydrochloride
[0078] 6
[0079] .alpha.-Azido-pinacolone (128.5 g, 0.911 mol) was combined
in 4.2 L of methanol with 77.1 mL of concentrated HCl and 15.42 g
of 10% Pd/C. The reaction mixture was stirred under hydrogen for
1.5 hours. The catalyst was removed by filtration. The solvent was
distilled to give a wet solid. The residual water was
azeotropically removed with isopropanol (2.times.500 mL).
Tert-butyl methyl ether (300 mL) was added and the resulting slurry
was stirred, filtered, washed with t-butyl methyl ether
(3.times.100 mL) and dried to give 131.0 g (95.5%) of the title
compound.
EXAMPLE 4
B' Preparation of .alpha.-Amino-pinacolone Hydrochloride
[0080] 7
[0081] .alpha.-Hexamethylenetetramino-pinacolone bromide (400 g,
1.254 mol, 1 eq) was combined in 2 L of ethanol with 12 N aqueous
HCl (439 mL, 5.26 mol, 4.2 eq). The reaction was stirred at
75.degree. C. for 1 hour and then allowed to cool to room
temperature, the resulting slurry filtered, the filtrate
concentrated in vacuo and isopropyl alcohol was added. The solution
was filtered again. Addition of 1.2 L of ether caused the desired
material to precipitate from solution. The material was filtered,
washed with ether (2.times. 300 mL), and dried in vacuo at
50.degree. C. overnight to provide 184.1 g (97%) of the title
compound.
EXAMPLE 5
C. Preparation of .alpha.-N-(2-Chloroacetylamino)-pinacolone
[0082] 8
[0083] The title compound of Example 4 (130.96 g, 0.8637 mol, 1 eq)
was dissolved in 3.025 L of CH.sub.2Cl.sub.2 under N.sub.2 at
-5.degree. C. Triethylamine (301 mL, 2.16 mol, 2.5 eq) was added,
followed by chloroacetyl chloride (75.7 mL, 0.450 mol, 1.1 eq) in
175 mL of CH.sub.2Cl.sub.2. The resulting slurry was stirred at -5
to -10.degree. C. for 2 hours. Water (1.575 L) was added, followed
by 175 mL of concentrated HCl. The organic phase was washed a
second time with 1.75 L of 10% aqueous HCl, and then with 500 mL of
water. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to provide 155.26 g (93.8%) of the title
compound. HPLC R.T.=2.27 min (Phenomenex Inc., 5 .mu.m C18 column
4.6.times.50 mm, 10-90% aqueous methanol over 4 minutes containing
0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
EXAMPLE 6
D. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Chloride
[0084] 9
[0085] The title compound of Example 5 (180.13 g, 0.9398 mol, 1 eq)
was combined with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq)
under N.sub.2. The reaction was heated at 105.degree. C. for 1
hour, the mixture was cooled to room temperature, and quenched with
1.3 kg of ice. The aqueous phase was extracted with ethyl acetate
(1 L, then 2.times.500 mL). The organic extracts were washed with
saturated aqueous NaHCO.sub.3 (4.times.1 L) which was
back-extracted several times with ethyl acetate. The organic phases
were combined, washed with saturated aqueous NaHCO.sub.3 (500 mL)
followed by saturated aqueous NaCl (300 mL), dried over MgSO.sub.4,
and concentrated in vacuo to give a brown oil. The crude material
was distilled under high vacuum at 100.degree. C. to provide 155.92
g (96%) of the title compound. HPLC R.T.=3.62 min (Phenomenex Inc.,
5 .mu.m C18 column 4.6.times.50 mm, 10-90% aqueous methanol over 4
minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at
220 nm).
[0086] Alternatively, the title compound of Example 5 (10.0 g,
52.17 mmol, 1 eq.) in 50 mL of tetrahydrofuran (THF) was combined
with (methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess'
reagent, 105.70 mmol, 2.03 eq., generated in situ from 9.2 mL of
chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of
triethylamine in 100 mL THF). The reaction was heated to 45.degree.
C. for 1.5 hours. After cooling to room temperature, the reaction
was quenched with water (50 mL). The organic layer was separated
and washed with saturated NaHCO.sub.3 (2.times.50 mL) and water (50
mL), dried over MgSO.sub.4 and passed through a small silica gel
plug. The solvent was removed to give an oil which was taken up in
a mixture of 15 mL heptane and 90 mL of t-butyl methyl ether, and
then washed with 0.2 N HCl (2.times.25 mL), saturated brine (25 mL)
and dried (MgSO.sub.4). Filtration and removal of solvent gave 10.9
g of the title compound.
EXAMPLE 7
E. Preparation of 5-(t-Butyl)-2-oxazolylmethyl Thiouronium
Hydrochloride
[0087] 10
[0088] The title compound of Example 6 (1.77 g, 10.2 mmol, 1.02 eq)
was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under N.sub.2
in 10 mL of absolute ethanol. The reaction was heated at reflux for
1.5 hours. The mixture was cooled to room temperature and
concentrated in vacuo. Trituration of the resulting crude material
with t-butyl methyl ether provided 2.32 g (93%) of the title
compound. HPLC R.T.=2.05 min (Phenomenex Inc., 5 .mu.m C18 column
4.6.times.50 mm, 10-90% aqueous methanol over 4 minutes containing
0.2% phosphoric acid, 4 mL/min, monitoring at 220 mn); .sup.1H NMR
(d.sub.6-DMSO): .delta. 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H),
1.24 (s, 9H).
EXAMPLE 8
F. Preparation of
5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-aminothiazole
[0089] 11
[0090] The title compound of Example 7 (1.25 g, 5 mmol, 1 eq) was
added to a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL),
toluene (10 mL) and tetrabutylammonium sulfate (50 mg, 0.086 mmol,
0.017 eq). 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1
eq) was added and the reaction was stirred at room temperature for
14.5 hours. The mixture was diluted with water and extracted twice
with ethyl acetate, the organic extracts washed with water
(4.times.10 mL), dried over MgSO.sub.4 and concentrated in vacuo to
provide 1.1 g (82%) of the title compound. HPLC 86.3% at 2.75 min
(Phenomenex Inc., 5 .mu.m C18 column 4.6.times.50 mm, 10-90%
aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4
mL/min, monitoring at 220 nm); .sup.1H NMR (CDCl.sub.3):
.delta.6.97 (s, 1H), 6.59 (s, 1H), 5.40 (br s, 2H), 3.89 (s, 2H),
1.27 (s, 9H).
EXAMPLE 9
G. Preparation of
5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-[(N-t-butoxycarbo-
nyl)-azacycloalkanoyl] Aminothiazole
[0091] 12
[0092] The title compound of Example 8 (9.6 g, 35.6 mmol) was
dissolved in N,N-dimethylformamide (36 mL) and CH.sub.2Cl.sub.2
(100 mL), to which was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8
g, 72 mmol, 2 eq), N-t-butoxycarbonyl-azacycloalkanoic acid (12.6
g, 55 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (2 g, 16 mmol,
0.45 eq). The clear reaction mixture became cloudy as it was
stirred at room temperature for 3.5 hours. Water (300 mL) and ethyl
acetate (200 mL) were added and the resulting precipitate was
removed by filtration. The filtrate was extracted with ethyl
acetate, the organic extracts dried over MgSO.sub.4 and
concentrated in vacuo to provide a yellow solid which was combined
with the precipitate obtained by filtration. The solid was boiled
in a mixture of ethanol, acetone and water for 20 minutes,
filtered, washed with an ethanol/water mixture and dried to give
16.6 g (97%) of the title compound.
EXAMPLE 10
H. Preparation of
5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-(azacycloalkanoyl-
)aminothiazole Hydrochloride
[0093] 13
[0094] The title compound of Example 9 (16.6 g) was dissolved in
150 mL of CH.sub.2Cl.sub.2, trifluoroacetic acid (30 mL) was added
dropwise, and the mixture was stirred at room temperature for 2
hours. The reaction was concentrated in vacuo, diluted with water
(300 mL), cooled in ice, made basic with sodium hydroxide, and the
resulting solid filtered and recrystallized from ethanol, water and
methanol to provide 11.2 g (83%) of the title compound as a yellow
solid. The white solid hydrochloride could be obtained by addition
of 18 mL of 1N aqueous HCl to 7 g of this material in methanol. MS:
381 [M+H].sup.+; HPLC: 100% at 3.12 min (YMC S5 ODS column
4.6.times.50 mm, 10-90% aqueous methanol over 4 minutes containing
0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
[0095] In the foregoing, there has been provided a detailed
description of particular embodiments of the present invention for
the purpose of illustration and not limitation. It is to be
understood that all other modifications, ramifications and
equivalents obvious to those having skill in the art based on this
disclosure are intended to be included within the scope of the
invention as claimed.
* * * * *