U.S. patent application number 09/991143 was filed with the patent office on 2002-03-28 for processes for preparing 3-arylsulfur hydroxamic acids.
This patent application is currently assigned to Syntex (U.S.A.) Inc.. Invention is credited to Campbell, Jeffrey Allen, Dvorak, Charles Alois, Fisher, Lawrence Emerson, McGrane, Paul Leo.
Application Number | 20020038037 09/991143 |
Document ID | / |
Family ID | 22219538 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020038037 |
Kind Code |
A1 |
Campbell, Jeffrey Allen ; et
al. |
March 28, 2002 |
Processes for preparing 3-arylsulfur hydroxamic acids
Abstract
This invention provides processes for the preparation of a
compound of Formula I:
Y--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2--S(O).sub.nR.sup.3
wherein: Y is hydroxy or XONX, where each X is independently
hydrogen, lower alkyl or lower acyl; R.sup.1 is hydrogen or lower
alkyl; R.sup.2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, or R.sup.1 and R.sup.2 together with the carbon
atom to which they are attached form a cycloalkyl or heterocyclo
group; R.sup.3 is aryl; and n is 0, 1 or 2. The invention also
provides novel aryl haloalkyl sulfide intermediates useful for the
preparation of compounds of Formula I and novel methods of
preparing aryl alkyl sulfides.
Inventors: |
Campbell, Jeffrey Allen;
(Cheshire, CT) ; Fisher, Lawrence Emerson;
(Mountain View, CA) ; Dvorak, Charles Alois; (Palo
Alto, CA) ; McGrane, Paul Leo; (Mountain View,
CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Syntex (U.S.A.) Inc.
Palo Alto
CA
|
Family ID: |
22219538 |
Appl. No.: |
09/991143 |
Filed: |
November 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09991143 |
Nov 9, 2001 |
|
|
|
09335447 |
Jun 17, 1999 |
|
|
|
60089778 |
Jun 18, 1998 |
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Current U.S.
Class: |
548/530 ;
562/429; 562/621 |
Current CPC
Class: |
C07C 323/20 20130101;
C07C 319/14 20130101; C07C 319/20 20130101; C07D 309/08
20130101 |
Class at
Publication: |
548/530 ;
562/429; 562/621 |
International
Class: |
C07D 27/12; C07C
323/50 |
Claims
What is claimed is:
1. A process for the preparation of a compound of Formula I:
Y--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2--S(O).sub.nR.sup.3
wherein: Y is hydroxy or XONX--, where each X is independently
hydrogen, lower alkyl or lower acyl; R.sup.1 is hydrogen or lower
alkyl; R.sup.2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, or R.sup.1 and R.sup.2 together with the carbon
atom to which they are attached form a cycloalkyl or heterocyclo
group; R.sup.3 is aryl; and n is 0, 1 or 2; comprising the steps
of: (1) alkylating a compound of Formula II,
RO--C(.dbd.O)--CH(R.sup.1)(R.sup.2), where R is alkyl or hydrogen,
with an arylmethylthio derivative of Formula III, ArSCH.sub.2--Z,
wherein Ar is an aryl group and Z is a leaving group, to provide a
compound of Formula IV, RO--C(.dbd.O)--C(R)(R.sup.2)--CH.sub.2SAr;
and (2) converting the compound of Formula IV to a compound of
Formula I by replacing the group RO-- with XONX-- and optionally
oxidizing the ArS group.
2. The method of claim 1, wherein: Ar has the formula
Ar.sup.1--A--Ar.sup.2 where Ar.sup.1 and Ar.sup.2 are phenyl rings,
each independently optionally substituted and A is a bond,
--CH.sub.2-- or --O--.
3. The method of claim 2, wherein Z is halo.
4. The method of claim 3, wherein: A is oxygen; Ar.sup.1 is phenyl;
and Ar.sup.2 is 4-chlorophenyl.
5. The method of claim 4, wherein the optional oxidation in step
(2) provides a compound of Formula I where n=2.
6. The method of claim 5, wherein R.sup.1 and R.sup.2 together with
the carbon atom to which they are attached form a heterocyclo
group.
7. The method of claim 6, wherein the heterocyclo group formed by
R.sup.1 and R.sup.2 is tetrahydropyranyl.
8. The method of claim 7, wherein the compound of Formula I is
4-[4-(4-chlorophenoxy)phenylsulfonylnethyl]-4-(N-hydroxycarboxamido)
tetrahydropyran.
9. The method of claim 2, which further comprises forming the
compound of Formula III, Ar.sup.1--A--Ar.sup.2--SCH.sub.2--Z by:
(i) treating a compound of Formula VI,
Ar.sup.1--A--Ar.sup.2--S(O).sub.2Cl with trimethyl phosphite, (ii)
optionally, followed by treatment with a base, and (iii)
oxidation.
10. The method of claim 9, wherein: Ar.sup.1 is phenyl; Ar.sup.2 is
4-chlorophenyl; A is oxygen; R.sup.1 and R.sup.2 together with the
carbon atom to which they are attached form a tetrahydropyranyl
group; and Y is HONH.
11. The method of claim 4, wherein step (1) comprises converting a
compound of Formula II to a silylketene acetal of Formula V,
RO(OTMS)C.dbd.CR.sup.1R.sup.2, and alkylating the silylketene
acetal with a compound of Formula III.
12. The method of claim 4, wherein step (1) comprises alkylating an
enolate of a compound of Formula II with a compound of Formula
III.
13. A method of preparing a compound of Formula ArSCH.sub.3,
wherein Ar is an aryl group, by treating a compound of Formula
ArSO.sub.2Cl with trimethyl phosphite and optionally, followed by a
base, to form a compound of Formula ArSCH.sub.3.
14. The method of claim 13, wherein Ar has the formula
Ar.sup.1--A--Ar.sup.2, where Ar.sup.1 and Ar.sup.2 are phenyl
rings, each independently optionally substituted and A is a bond,
CH.sub.2 or --O--.
15. The method of claim 14, wherein: A is oxygen; Ar.sup.1 is
phenyl; and Ar.sup.2 is 4-chlorophenyl.
16. A compound ZCH.sub.2S--Ar.sup.1--A--Ar.sup.2, wherein: Ar.sup.1
and Ar.sup.2 are independently optionally substituted phenyl; Z is
halo; and A is oxygen or CH.sub.2.
17. The compound of claim 16, wherein: Ar.sup.1 is phenyl; Ar.sup.2
is halophenyl; and A is oxygen.
18. The compound of claim 17 wherein Ar.sup.2 is chlorophenyl, and
Z is chloro, i.e., 4-(4-chlorophenoxy)phenyl chioromethyl
sulfide.
19. The compound which is 4-(4-chlorophenoxy)phenyl methyl sulfide.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. 119(e)
of U.S. Provisional Application Ser. No. 60/089,778, filed Jun. 18,
1998, hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods of preparing matrix
metalloprotease inhibitors, particularly 3-arylsulfur hydroxamic
acids.
[0004] 2. Background Information
[0005] I. MMP Inhibitors
[0006] Matrix metalloproteases ("MMPs") are a family of proteases
(enzymes) involved in the degradation and remodeling of connective
tissues. MMP expression is stimulated by growth factors and
cytokines in the local tissue environment, where these enzymes act
to specifically degrade protein components of the extracellular
matrix, such as collagen, proteoglycans (protein core), fibronectin
and laminin. Excessive degradation of extracellular matrix by MMPs
is implicated in the pathogenesis of many diseases, including
rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone
resorptive diseases (such as osteoporosis), chronic obstructive
pulmonary disease, cerebral hemorrhaging associated with stroke,
periodontal disease, aberrant angiogenesis, tumor invasion and
metastasis, corneal and gastric ulceration, ulceration of skin,
aneurysmal disease, and in complications of diabetes.
[0007] Furthermore, inhibitors of MMP also are known to
substantially inhibit the release of tumor necrosis factor (TNF)
from cells and therefore may be used in the treatment of conditions
mediated by TNF. Such uses include, but are not limited to, the
treatment of inflammation, fever, cardiovascular effects,
hemorrhage, coagulation and acute phase response, cachexia and
anorexia, acute infections, shock states, restenosis, graft versus
host reactions and autoimmune disease.
[0008] MMP inhibition is, therefore, recognized as a good target
for therapeutic intervention. Consequently, inhibitors of MMPs
provide useful treatments for diseases associated with the
excessive degradation of extracellular matrix and diseases mediated
via TNF and several MMP inhibitors are currently being developed
for such uses.
[0009] One particular class of MMP inhibitors are the 3-arylsulfur
hydroxamic acids described in EP 0 780 386 A1, published Jun. 25,
1997. This publication discloses MMP inhibitors of Formula I,
Y--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2--S(O).sub.nR.sup.3
[0010] where n, Y, R.sup.1, R.sup.2 and R.sup.3 are as described
below in the Summary of the Invention.
[0011] WO 97/24117, published Jul. 10, 1997, discloses 3-aryl
sulfur hydroxamic acids of formula,
HON(H)--C(.dbd.O)--C.sub.p(R.sub.1)(R.sub.2)-
--C(R.sub.3)(R.sub.4)--S(O).sub.n--C.sub.m(R.sub.5)(R.sub.6)--Ar,
where p, m, n and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6 and Ar are as described in WO 97/24117.
[0012] WO 98/05635, published Feb. 12, 1998, discloses 3-arylsulfur
hydroxamic acids of formula
B--S(O).sub.0-2--CHR.sup.1--CH.sub.2--CO--NHO- H, where B and
R.sup.1 are as described in in WO 98/05635.
[0013] WO 98/13340, published Apr. 2, 1998, discloses
.beta.-sulfonyl hydroxamic acids of
HONHC(.dbd.O)--CHR.sub.2--CH.sub.2--S(O).sub.2R.sub.1 where R.sub.1
and R.sub.2 are as described therein.
[0014] However, the processes disclosed in these publications for
preparing 3-arylsulfur hydroxamic acids proceed via the
nucleophilic attack of a thiol on the .beta.-carbon of a
carboxylate derivative, either displacing a leaving group at the
.beta.-carbon or performing a Michael reaction on an .alpha.,.beta.
unsaturated ester or acid. Thus, the disclosed processes are
limited by the availability of the corresponding thiols and the
.beta.-substituted carboxylate derivatives and .alpha.,.beta.
unsaturated esters. This invention provides novel processes and
novel intermediates that are not dependent on the availability of
the reagents used in the above publications.
[0015] The use of 3-arylsulfonyl hydroxamic acids as MMP inhibitors
is also described in WO 97/49679 A1, published Dec. 31, 1997.
[0016] II. Preparation of Aryl Alkyl Sulfides
[0017] Aryl haloalkyl sulfides are valuable intermediates in
synthetic organic processes and they are commonly made by free
radical halogenation of a precursor aryl alkyl sulfide. The aryl
alkyl sulfide is in turn typically available via sulfonation of a
precursor aryl hydrocarbon, reduction to an aryl thiol and
alkylation of the thiol. It would be useful to have methods of
directly converting arylsulfonyl derivatives to aryl methyl
sulfides.
[0018] There have been various reports of the reactions between
trialkyl phosphites and aryl sulfonyl derivatives. See, for
example, R. W. Hoffman, T. R. Moore and B. J. Kagan, ("The Reaction
between Triethyl Phosphite and and Alkyl and Aryl Sulfonyl
Chlorides") J. Am. Chem. Soc., 78:6413-6414 (1956); J. M. Klunder
and K. Barry Sharpless, ("A Convenient Synthesis of Sulfinate
Esters from Sulfonyl Chlorides") J. Org. Chem., 52:2598-2602
(1987); and J. Cadogan ("Oxidation of Tervalent Organic Compounds
of Phosphorous") Quarterly Reviews, 16:208-239 (1962). The reaction
of benzensulfenyl chloride with triethylphosphite to yield ethyl
phenyl sulfide has also been reported, T. Mukaiyama and H. Ueki,
("The Reactions of Sulfur-containing Phosphonium Salts") Tetr.
Lett., 35:5429-5431 (1967). Aryl sulfonyl chlorides have also been
converted to aryl methyl sulfides in three steps by treatment of an
aryl sulfonyl chloride with lithium diphenylphosphide, Ph.sub.2PLi,
to afford a P-diphenyl-aryl sulfophosphamide followed by cathodic
reduction and methylation of the resulting aryl thiolate, J. Pilard
and J. Simonet. ("The Cathodic Cleavage of the S--P Bond. Synthesis
and Electrochemical Behaviour of Sulfonamide Phosphorous
Analogues"), Tetr. Lett., 38(21):3735-3738 (1997).
SUMMARY OF THE INVENTION
[0019] In one aspect, this invention provides processes for the
preparation of a compound of Formula I:
Y--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2--S(O).sub.nR.sup.3
Formula I
[0020] wherein:
[0021] Y is hydroxy or XONX--, where each X is independently
hydrogen, lower alkyl or lower acyl;
[0022] R.sup.1 is hydrogen or lower alkyl;
[0023] R.sup.2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, or R.sup.1 and R.sup.2 together with the carbon
atom to which they are attached form a cycloalkyl or heterocyclo
group;
[0024] R.sup.3 is aryl; and
[0025] n is 0, 1 or 2;
[0026] comprising the steps of:
[0027] (1) alkylating a compound of Formula II,
RO--C(.dbd.O)--CH(R.sup.1)(R.sup.2) Formula II
[0028] where R is alkyl or hydrogen, with an arylmethylthio
derivative of Formula m, ArSCH.sub.2--Z, wherein Ar is an aryl
group and Z is a leaving group, to provide a compound of Formula
IV,
RO--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2SAr, and Formula IV
[0029] (2) converting the compound of Formula IV to a compound of
Formula I by replacing the group RO-- with XONH-- and optionally
oxidizing the ArS group as necessary in either order.
[0030] The invention also provides novel aryl haloalkyl sulfide and
aryl alkyl sulfide intermediates useful for the preparation of
compounds of Formula I and novel methods of preparing aryl alkyl
sulfides.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Definitions
[0032] As usedherein, the term "(C.sub.p-q) alkyl" means a linear
or branched fully-saturated hydrocarbon radical having p to q
carbon atoms; for example, a "C.sub.1-4 alkyl" means a linear or
branched fully saturated hydrocarbon radical having one to four
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, or
tert-butyl.
[0033] Unless otherwise specified, the term "lower alkyl" means a
C.sub.1-4 alkyl radical.
[0034] As used herein, the term "(C.sub.3-6) cycloalkyl" means a
fully saturated cyclic hydrocarbon radical of three to six ring
carbon atoms, e.g., cyclopropyl, cyclopentyl and the like.
[0035] As used herein, the term "lower acyl" refers to a group
--C(.dbd.O)R, where R is a (C.sub.1-4)alkyl radical.
[0036] As used herein, the term "loweralkoxy" refers to a group
--OR, where R is a (C.sub.1-4)alkyl radical.
[0037] As used herein, the term "(C.sub.7-10)alkoxy" refers to a
group OR, where R is a (C.sub.7-10)alkyl radical.
[0038] As used herein, the term "aryl" means a monovalent
monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring
atoms, and optionally substituted independently with one, two or
three substituents selected from alkyl, haloalkyl, cycloalkyl,
halo, nitro, cyano, optionally substituted phenyl, --OR (where R is
hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted
phenyl), acyl, --COOR (where R is hydrogen or alkyl). More
specifically the term aryl includes, but is not limited to, phenyl,
1-naphthyl, 2-naphthyl, and derivatives thereof.
[0039] As used herein, the term "arylene" means a divalent
monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring
atoms, and optionally substituted independently with one, two or
three substituents selected from alkyl, haloalkyl, cycloalkyl,
halo, nitro, cyano, optionally substituted phenyl, --OR (where R is
hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted
phenyl), acyl, --COOR (where R is hydrogen or alkyl). More
specifically the term aryl includes, but is not limited to,
1,4-phenylene and 1,2 phenylene.
[0040] "Optionally substituted phenyl" means a phenyl group which
is optionally substituted independently with one, two or three
substituents selected from alkyl, haloalkyl, halo, nitro, cyano,
--OR (where R is hydrogen or alkyl), --NRR' (where R and R' are
independently of each other hydrogen or alkyl), --COOR (where R is
hydrogen or alkyl) or --CONR'R" (where R' and R" are independently
selected from hydrogen or alkyl).
[0041] "Heterocyclo" means a saturated monovalent cyclic group of 3
to 8 ring atoms in which one or two ring atoms are heteroatoms
selected from N, O, or S(O).sub.n, where n is an integer from 0 to
2, the remaining ring atoms being C. The heterocyclo ring may be
optionally fused to a benzene ring or it may be optionally
substituted independently with one or more substituents, preferably
one or two substituents, selected from alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, halo, cyano, acyl,
monosubstituted amino, disubstituted amino, carboxy, or
alkoxycarbonyl. More specifically the term heterocyclo includes,
but is not limited to, pyrrolidino, piperidino, morpholino,
piperazino, tetrahydropyranyl, and thiomorpholino, and the
derivatives thereof.
[0042] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry i.e., an atom or group
capable of being displaced by a nucleophile and includes halogen,
alkanesulfonyloxy, arenesulfonyloxy, amino, alkylcarbonyloxy,
arylcarbonyloxy, such as chloro, bromo, iodo, mesyloxy, tosyloxy,
trifluorosulfonyloxy, N,O-dimethylhydroxylamino, acetoxy, and the
like.
[0043] In one aspect, this invention provides a process for the
preparation of a compound of Formula I:
Y--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2--S(O).sub.nR.sup.3
Formula I
[0044] wherein:
[0045] Y is hydroxy or XONX, where each X is independently
hydrogen, lower alkyl or lower acyl;
[0046] R.sup.1 is hydrogen or lower alkyl;
[0047] R.sup.2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, or R.sup.1 and R.sup.2 together with the carbon
atom to which they are attached form a cycloalkyl or heterocyclo
group;
[0048] R.sup.3 is aryl; and
[0049] n is 0, 1 or 2;
[0050] comprising the steps of:
[0051] (1) alkylating a compound of Formula II,
RO--C(.dbd.O)--CH(R.sup.1)(R.sup.2) Formula II
[0052] where R is alkyl or hydrogen, with an arylmethylthio
derivative of Formula III, ArSCH.sub.2--Z, wherein Ar is an aryl
group and Z is a leaving group, to provide a compound of Formula
IV,
RO--C(.dbd.O)--C(R.sup.1)(R.sup.2)--CH.sub.2SAr and Formula IV
[0053] (2) converting the compound of Formula IV to a compound of
Formula I by replacing the group RO-- with XONH-- and optionally
oxidizing the ArS group as necessary in either order.
[0054] Unlike the methods disclosed in EP 0 780 386 A1, published
Jun. 25, 1997, WO 97/24117, published Jul. 10, 1997, WO 98/05635,
published Feb. 12, 1998 and WO 98/13340, published Apr. 2, 1998,
for the synthesis of 3-arylsulfur hydroxamic acids, the processes
of the present invention proceed via the alkylation of the
.alpha.-carbon of a carbonyl group with a halomethyl aryl sulfide.
The invention also provides novel halomethyl aryl sulfides, such as
chlorophenoxyphenyl chloromethyl sulfide and methods for their
preparation. Thereby, the inventors are able to prepare compounds
of Formula I by novel processes not previously available.
[0055] These reaction processes are shown in Scheme A, below. 1
[0056] Compounds of Formula IV may be converted to compounds of
Formula I by conversion of the carboxyl group to a group
--C(.dbd.O)--L where L is a leaving group under nucleophilic
displacement conditions followed by displacement of L with
hydroxylamine (or an alkylated derivative). The resulting
hydroxamic acid is then oxidized as necessary to give the desired
sulfoxide or sulfone. Oxidation to the sulfoxide is accomplished by
treatment with mild oxidizing agents such as sodium or potassium
metaperiodate or one equivalent potassium peroxymonosulfate
(Oxone.TM.). Other oxidants that may be used include peracids,
(e.g. performic or peracetic acid) or sodium perborate/organic acid
mixtures (e.g. performic or peracetic acid). The reaction may be
halted at the sulfoxide stage by limiting the quantity of reagents,
temperature and reaction time. Further oxidation to the sulfone is
accomplished by treatment under more vigorous conditions with
organic peracids such as m-chloroperbenzoic acid or two equivalents
of sodium peroxymonosulfate. Alternatively, other oxidizing agents
such as perborates, e.g., sodium perborate, in a carboxylic acid
solvent such as formic, acetic or propionic acid may be used. These
last two steps may also be reversed, i.e., oxidation of the sulfur
moiety may precede conversion of the acid to the hydroxamate.
However, overall yields are usually higher with the former
sequence.
[0057] Compounds of Formula II,
RO--C(.dbd.O)--CH(R.sup.1)(R.sup.2), can be purchased from
commercial suppliers or are readily available by published
procedures known to one of skill in the art. See, for example, EP 0
780 386 A1.
[0058] Compounds of Formula III, ArSCH.sub.2--Z, are made by
oxidation of the precursor arylmethylthioether. Compounds
ArSCH.sub.2Cl are made by oxidation with sulfuryl chloride in
aprotic solvents such as methylene chloride, t-butylmethyl ether or
hexane. The oxidation may be done at room temperature or at lower
temperatures, e.g., from about 0-10.degree. C. Other reagents, such
as N-chlorosuccinimide, may also be used. Compounds ArSCH.sub.2Br
are made by oxidation with sulfuryl bromide or other reagents such
as N-bromosuccinimide.
[0059] Compounds of Formula II, ArSCH.sub.2--Z, where Z is chloro
or bromo may also be made from the corresponding thiol as shown
below: 2
[0060] Arylmethylthioethers are generally available either from
commercial vendors or published literature procedures. For example,
they may be made by sulfonylating an aryl compound to the
corresponding sulfonic acid, reducing the sulfonic acid to a thiol
and methylating the thiol.
[0061] Alternatively, as shown in Scheme B, the inventors have
unexpectedly discovered that arylsulfonyl halides can be converted
directly to arylmethylthioethers in one step by treatment with
trimethylphosphite. The conversion proceeds best if the
trimethylphosphite treatment is followed by treatment with a base.
Either an organic base such as an alkylamine (e.g. triethylamine)
or a hydroxylic base such as an alkali metal hydroxide or an
alkaline earth metal hydroxide may be used. However, the conversion
may also be accomplished, albeit in somewhat lower yield, without
the addition of a base. In such processes, the yield of the aryl
methyl sulfide may be increased by heating to elevated
temperatures, e.g., as high as about 100.degree. C., preferably as
high as about 130.degree. C. (internal temperature). Consequently,
the invention also provides a novel method of preparing aryl methyl
sulfides by directly reducing/alkylating an arylsulfonyl halide
with trimethyl phosphite. 3
[0062] The method is particularly useful for for forming compounds
of formula ArSCH.sub.3, wherein Ar has the formula
Ar.sup.1--A--Ar.sup.2, where Ar.sup.1 and Ar.sup.2 are phenyl
rings, each independently optionally substituted and A is a bond,
CH.sub.2 or--O--, and more particularly where, A is oxygen,
Ar.sup.1 is phenyl and Ar.sup.2 is 4-chlorophenyl.
[0063] Subsequent halogenation of ArSCH.sub.3 then provides key
intermediates of formula ArSCH.sub.2--X where X is halo. Useful key
intermediates include those where Ar is Ar.sup.1--A--Ar.sup.2,
wherein Ar.sup.1 and Ar.sup.2 are independently optionally
substituted phenyl, X is halo, A is oxygen, or CH.sub.2. A
particularly useful intermediate is that wherein Ar.sup.1 is
phenyl, Ar.sup.2 is halophenyl, and A is oxygen.
[0064] Alkylation of a compound of Formula II with a compound of
Formula III may be accomplished by conditions known to one of skill
in the art such as converting a compound of Formula II to an
enolate or enol followed by reaction with a compound of Formula
III. Other conditions include forming the dianion of the acid
(i.e., compound of Formula II where R.dbd.H) by treatment with two
equivalents of a base such as lithium diisopropylamide or lithium
hexamethyldisilazide and alkylating with one equivalent of a
compound of Formula III.
[0065] In one embodiment, a compound of Formula II was converted to
a silylketene acetal as shown in Reaction Scheme C (where Silyl
represents a silyl group), followed by Mukaiyama coupling of the
acetal with a compound of Formula III. The coupling is generally
done in an anhydrous aprotic solvent such as a halocarbon or
hydrocarbon (methylene chloride, chloroform, benzene, toluene etc.)
in the presence of a Lewis acid such as zinc chloride, zinc
bromide, zinc iodide, ferric bromide or titanium tetrachloride.
Silylketene acetals may be readily prepared from compounds of
Formula II by procedures such as those described in C. Ainsworth,
F. Chen, Y. N. Kuo "Ketene Alkyltrialkylsilyl Acetals: Synthesis,
Pyrolysis and NMR Studies") J. Organometallic Chem., 46:59-87
(1972). A variety of silyl protecting groups, e.g.,
t-butyldimethylsilyl, trimethylsilyl, etc. may be used. Silylketene
acetals can be formed from either the ester (R=alkyl) or acids
(R.dbd.H) of Formula II. Formation of the silylketene acetal from
the acid may be accomplished using two equivalents of base and
quenching with two equivalents of the silylating reagent.
Subsequent alkylation with a compound of Formula II followed by a
hydrolytic work up then directly yields a carboxylic acid of
Formula IV. Reagents that may be used to form the silylketene
acetal include trimethylysilyl triflate, trimethylsilyl chloride or
bromide, tert-butyldimethylsilyl chloride and bis-trimethylsilyl
acetamide. 4
[0066] Alternatively, an enolate of a compound of Formula II may be
directly alkylated with a compound of Formula III, thus avoiding
the intermediacy of the silylketene acetal. The enolate is formed
under standard conditions, by treatment with a non-nucleophilic
organic base such as lithium diisopropylamide or lithium
hexamethyldisilazide, or a metal hydride such potassium hydride,
under anhydrous conditions, typically at room temperature, in a
polar aprotic solvent such as tetrahydrofuran, dimethoxyethane or
glyme and the like. Subsequent addition of a compound of a Formula
III followed by heating if necessary to reflux temperatures, e.g.,
60-80.degree. C., provides an alkylated product of Formula IV. The
enolate may also be formed from the corresponding a-bromoester of a
compound of Formula II by treatment with zinc to form the zinc
enolate which can then be alkylated.
[0067] Though the processes described herein may be used to prepare
a variety of 3-arylsulfur hydroxamic acids and their corresponding
carboxy and ester derivatives, they are particularly useful for
preparing compounds of Formula I wherein the aryl group Ar is of
the formula Ar.sup.1--A--Ar.sup.2, wherein Ar.sup.1 and Ar.sup.2
are phenyl rings, each independently optionally substituted and A
is a bond, --CH.sub.2-- or --O--.
[0068] Other useful compounds that may be made by the methods of
the invention include compounds of Formula I where R.sup.1 and
R.sup.2 together with the carbon atom to which they are attached
form a cycloalkyl or heterocyclo group, particularly a
tetrahydropyranyl group.
[0069] Additional useful hydroxamic acids that may be prepared
include those that are .alpha.,.alpha.-disubstituted, i.e., neither
R.sup.1 nor R.sup.2 are hydrogen.
[0070] Utility and Administration
[0071] As described earlier, the compounds made by these processes
are MMP inhibitors, useful in treating a variety of diseases as
disclosed in EP 0 780 386 A1, published Jun. 25, 1997; WO 97/24117,
published Jul. 10, 1997; and WO 98/05635, published Feb. 12,
1998.
[0072] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
[0073] Abbreviations used in the examples are defined as follows:
"DMF" for dimethylformamide, "NaOH" for sodium hydroxide, "DMSO"
for dimethylsulfoxide, "PTLC" for preparatory thin layer
chromatography, "EtOAc" for ethyl acetate, "LDA" for lithium
diisopropylamide and "TMSCl" for trimethylsilylchloride.
EXAMPLE
Synthesis of
4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarbo-
xamido) tetrahydropyran.
[0074] Scheme D shows a representative method of this invention for
the preparation of
14,4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydrox-
ycarboxamido) tetrahydropyran, a compound of Formula I,
wherein:
[0075] Y is NHOH;
[0076] R.sup.1 and R.sup.2 together with the carbon atom to which
they are attached represent a tetrahydropyran-4-yl group; and
[0077] R.sup.3 is 4-chlorophenoxyphenyl. 5
[0078] Although Scheme D is directed towards the synthesis of a
specific 3-arylsulfur hydroxamic acid, it is to be understood that
a similar set of reactions can be used to prepare other arylsulfur
hydroxamic acids, carboxylic acids and esters by substituting
appropriate starting materials and reagents as outlined in Reaction
Schemes A-C.
[0079] A. Preparation of 4-(4-Chlorophenoxy)phenyl Chloromethyl
sulfide
[0080] Step 1
[0081] Diphenylether 1, is available from Aldrich (Milawaukee,
Wis.) and can be converted to 4-(4'-chlorophenoxy)phenyl
sulfonylchloride, compound 3, using known procedures, such as
described in WO 97/20824.
[0082] Step 2
[0083] 4-(4'-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3,
was dissolved in three liters of toluene and the solution was added
dropwise, with stirring, to 3.6 kg of trimethyl phosphite which had
been preheated to 60.degree. C. The reaction was exothermic and the
reaction was allowed to heat to 80.degree.-90.degree. C. during the
addition. Thin layer chromatography indicated a mixture of the
desired thioether and two baseline products. The mixture was
refluxed until the pot temperature rose to .about.130.degree. C.
The mixture was cooled to .about.60.degree. C. and 1 liter of
methanol was added. Potassium hydroxide solution (4.5 kg of 45%
aqueous solution) was added dropwise, slowly, with rapid stirring
to the reaction mixture. The addition was very exothermic and the
pot temperature was controlled to 65.degree.-80.degree. C. The
mixture was then refluxed for 2 hrs. More toluene (6 liters) was
added and the mixture cooled to .about.60.degree. C. The lower
aqueous layer was separated and the organic layer washed with 3
liters of water. The organic layer was stripped to a low volume and
9 liters of isopropanol charged to the hot mixture. The solution
was distilled until .about.3.5 liters of distillate had been
collected. The mixture was held at 45.degree. C. for several hours
and was then cooled to -10.degree. C. and stirred several hours.
The white, crystalline product was collected, washed with cold
isopropanol and dried to yield 1.9 kg of 4-(4'-chlorophenoxy)phenyl
methyl sulfide, 4.
[0084] Step 3
[0085] Into a separate reactor was charged
4-(4'-chlorophenoxy)phenyl methyl sulfide, 4, and CH.sub.2Cl.sub.2
(26 Kg). The resultant solution was cooled to less than 10.degree.
C. and then treated with SO.sub.2Cl.sub.2 at such a rate so that
the temperature did not exceed 10.degree. C. (30 min. required for
the addition). An additional 2 Kg of CH.sub.2Cl.sub.2 was used to
rinse in the SO.sub.2Cl.sub.2. After stirring for 1 h, the mixture
was warmed to room temperature (degassing occurs) and then further
warmed to reflux for 30 minutes. Upon cooling to room temperature,
the product solution was washed with water (15.5 Kg) and then with
brine (10.3 Kg). The stirred organic solution was then treated with
a slurry of MgSO.sub.4 (2.6 kg) in CH.sub.2Cl.sub.2 (5 kg). The
drying was allowed to proceed overnight and the mixture was
filtered to remove the drying agent. The solids were washed with
CH.sub.2Cl.sub.2 (20.7 kg) and the combined organics were
concentrated to effect azeotropic drying (38 kg of distillate
collected, Karl Fischer shows 0.026% water in concentrate). The
product was treated with CH.sub.2Cl.sub.2 (19.8 kg) and then was
reconcentrated (19.8 kg distillate, Karl Fischer now at 0.014%).
HPLC analysis showed 94.7% 4-(4'-chlorophenoxy)phenyl chloromethyl
sulfide, 5.
[0086] B. Preparation of Silylketene Acetal
[0087] Steps 4 and 5
[0088] Tetrahydropyran-4-carboxylic acid ethyl ester, 9, was
prepared from commercially available diethylmalonate via steps 4
and 5 using known literature procedures as described in for
example, U.S. Pat. No. 5,412,120; 5,414,097; and EP584663 A2.
[0089] Step 6
[0090] To a nitrogen purged reactor was charged 26.8 kg (67.37
mole) of a solution of LDA. This was cooled to -15.degree. C. and
then a mixture of TMSCl (7.32 kg, 67.37 mole) and
tetrahydropyran-4-carboxylic acid ethyl ester, 9, (10.32 kg, 65.3
mole) was added at such a rate that the temperature did not exceed
-10.degree. C. (1 h addition time). An additional 0.2 kg of TMSCl
was added in one portion. The resultant mixture was heated to
20.degree. C. and, after 4 h, a vacuum of 28 mm Hg was applied. The
mixture was heated to 65.degree. C. to remove volatiles. Toluene
(11.95 kg) was added and the distillation continued. When no more
distillate collected, the mixture was cooled to 25.degree. C. A
slurry of celite (2.7 kg) in hexane (20.6 kg) was added. After
stirring 1 h, the mixture was filtered through a precoated Nutsche
filter (1.5 kg of celite in 5 kg of hexane for precoat). The
reactor was rinsed with hexane (11 kg), and this was used to rinse
the filter. The combined organics were concentrated to an oil using
19-25 mm Hg and mild heating. The concentrate was transferred to a
nitrogen purged storage vessel with the aid of CH.sub.2Cl.sub.2 (7
kg) to give 17.5 kg of a solution of silylketene acetal 10.
[0091] C. Preparation of
4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N--
hydroxycarboxamido) tetrahydropyran
[0092] Step 7
[0093] 90% of the silylketene acetal solution from Step 6 was
charged to the reactor containing 4-(4'-chlorophenoxy)phenyl
chloromethyl sulfide 5, followed directly by a slurry of ZnCl.sub.2
(0.59 kg, 4.34 mole) in CH.sub.2Cl.sub.2 (5 kg). The red reaction
mixture was heated to reflux for 14 h (minimal heating required
during first 1 h due to exotherm), at which point HPLC showed about
10% starting material. The remaining 10% of the ketene acetal was
added and the mixture was heated at reflux with collection of the
CH.sub.2Cl.sub.2 to a pot temperature of 68.degree. C. HPLC
analysis of an aliquot showed <1% starting material. Ethanol
(15.5 kg), water (20.6 kg), and 45% KOH (20.3 kg) were added to the
concentrated product mixture. The two phase mixture was stirred at
65.degree. C. overnight (17 h) and was then warmed to a pot
temperature of 90.degree. C. to complete the saponification and to
distill the ethanol. The mixture was cooled to 60-65.degree. C. and
hexane (41 kg) was added. After stirring 10 min. and then allowing
layer separation, the lower layer was transferred to another
reactor containing water (24 kg) and 37% HCl (21.6 kg).
Simultaneous with this transfer, EtOAc (134.5 kg) was pumped to the
receiving reactor. The hexane solution was washed once with
65.degree. C. water (25 liters) which was then transferred to the
receiving reactor. This reactor now contained an EtOAc solution of
the product acid and a lower aqueous layer. The lower layer was
separated and replaced with 50 L of 65.degree. C. water. After
stirring briefly, the layers were separated. The organic solution
was concentrated as much as possible using partial vacuum.
CH.sub.3CN (93.5 kg) was added and distillation continued at
atmospheric pressure to a final volume of 90 liters. The mixture
was cooled over 8 h to 5.degree. C. and was held there 8 h. The
solids were collected on a filter and were washed with CH.sub.3CN
(15 kg) and hexane (15.5 kg). After drying at 78.degree. C. and 24
mm Hg to constant mass, there was obtained 16.34 kg of the product
acid, 12, as a dense, slightly off-white solid. HPLC purity was
99%.
[0094] Step 8
[0095] A clean, dry 100 gallon reactor was charged with
4-carboxy-4-{4-(4-chlorophenoxyphenyl)thiomethyl}tetrahydropyran 12
(15.45 kg, 40.7 moles). To this reactor was added dichloromethane
(77.2 L, 102 kg). The suspended carboxylic acid was chilled to
0-5.degree. C. under N.sub.2 with agitation. A catalytic amount of
N,N-dimethylformamide (0.11) was charged, followed by slow addition
of oxalyl chloride (5.3 kg, 3.6 L). The contents of the reactor
were agitated and the internal temperature was allowed to rise to
ambient over a 4-12 hour period to allow conversion to the acid
chloride. Another clean, dry 100 gallon reactor was charged with
tert-butanol (26.8 kg, 34.5 L), tetrahydrofuran (75.4 kg, 84 L) and
hydroxylamine (50 aqueous, 17 kg, 15.8 L). The contents of this
reactor were agitated at ambient temperature. The contents of the
reactor containing the acid chloride were chilled to 0-5.degree. C.
Slow addition of the hydroxylamine solution is begun. The rate of
addition was regulated such that the internal temperature of the
acid chloride solution does not rise above 10.degree. C. When the
addition is complete, the contents of the reactor containing the
newly formed hydroxamic acid were warmed to 20-25.degree.. After a
check for reaction completeness (HPLC or TLC), the solvent was
removed in vacuo keeping the contents of this reactor below
45.degree. C. When little solvent is left to distill, the reactor
was charged with acetonitrile (48.6 kg, 61.7 L). The contents were
heated to reflux, and water (61.7 L) was added over a period of
30-50 minutes. The contents of the reactor were cooled to
0-5.degree. C. over a period of 2-4 hours and slowly agitated for
4-14 hours. The solid hydroxamic acid 13, was collected by
filtration and washed with water. Typically, the wetcake so
obtained is not dried but used as is. However, drying can be
accomplished in vacuo at ca 50.degree. C. The solid (21.5 kg wet,
14.45 , kg dry, 90.1%) was 99.8% pure by area normalization
HPLC.
[0096] Step 9
[0097] A clean, dry 100-gallon reactor was charged with oxone.RTM.
(potassium peroxymonosulfate, 37.07 kg, 60.3 moles). Deionized
water was added (88.3 kg) and the contents of the reactor were
agitated and heated (to ca. 35-40.degree. C.) to dissolve the
oxone. Another clean, dry 100 gallon reactor was charged with the
hydroxamic acid, 13, (21.18 kg waterdamp cake, 14.45 dry weight,
36.7 moles) and dissolved in N-methyl-2-pyrrolidinone (100.5 kg)
with agitation. The contents of this reactor were heated to
30-35.degree. C. The aqueous oxone.TM. solution was added to the
reactor containing the hydroxamic acid at such a rate that the
internal temperature did not exceed 49.degree. C. After the
addition of oxonetm was complete, the mixture was assayed by HPLC
and TLC. When the reaction was complete, typically in 0 to 1 hour
post addition (HPLC data area normalization purity is typically
>98.5% desired product) the product was treated with deionized
water (25 kg) and cooled to 20.degree. C. Crystallization of the
crude product typically occurred at 20-25.degree. C. (22.degree. C.
in this example). The mixture was then cooled to 5.degree. C. and
stirred for 10-14 hours (12 in this example). The precipitated
product was collected by filtration and washed well with deionized
water followed by hexanes. This wet cake (47.9 kg) was charged into
a clean, dry, residue free 100-gallon reactor. Ethyl acetate (140
kg) was charged to the solid followed by deionized water (120.6
kg). The contents of the reactor were agitated and heated (to ca
60.degree. C.). Agitation was stopped and the layers were allowed
to separate. The aqueous layer was separated. Optionally, this can
be followed by an aqueous NaHCO.sub.3 wash and water wash. The
organic layer was filtered through a 5-10.mu. cotton filter into a
clean, dry, residue free reactor. The mixture was concentrated in
vacuo to approximately 50% (ca 50 L) of the starting volume. The
solid was separated and recrystallized from ethyl acetate after
heating to approximately 70.degree. C. and cooling to 5.degree. C.
The solid was collected by filtration in a clean dry filter and
dried at 40-45.degree. C. under a nitrogen stream (an agitated
filter was used for this example). 11.82 kg of final product,
4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydrox-
ycarboxamido) tetrahydropyran, compound 14, was obtained in 75.6%
yield (99.8% pure by area normalization HPLC) upon vacuum
drying.
[0098] The foregoing invention has been described in some detail by
way of illustration and example, for the purposes of clarity and
understanding. It will be obvious to one of ordinary skill in the
art that changes and modifications may be practiced within the
scope of the appended claims. Therefore, it is to be understood
that the above description is intended to be illustrative and not
restrictive. The scope of the invention should, therefore, be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0099] The patents, patent applications and publications cited in
this application are hereby incorporated by reference in their
entirety for all purposes to the same extent as if each individual
patent, patent application or publication were so individually
denoted.
* * * * *