U.S. patent application number 13/490706 was filed with the patent office on 2013-05-09 for clean, high-yield preparation of s,s and r,s amino acid isosteres.
This patent application is currently assigned to Aerojet Fine Chemicals LLC. The applicant listed for this patent is Todd E. Clement, Aslam A. Malik, Hasan Palandoken, James Robinson, III, Joy A. Stringer. Invention is credited to Todd E. Clement, Aslam A. Malik, Hasan Palandoken, James Robinson, III, Joy A. Stringer.
Application Number | 20130116457 13/490706 |
Document ID | / |
Family ID | 26830230 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116457 |
Kind Code |
A1 |
Malik; Aslam A. ; et
al. |
May 9, 2013 |
CLEAN, HIGH-YIELD PREPARATION OF S,S AND R,S AMINO ACID
ISOSTERES
Abstract
The present invention provides compounds and methods that can be
used to convert the intermediate halomethyl ketones (HMKs), e.g.,
chloromethyl ketones, to the corresponding S,S- and
R,S-diastereomers. More particularly, the present invention
provides: (1) reduction methods; (2) inversion methods; and (3)
methods involving the epoxidation of alkenes. Using the various
methods of the present invention, the R,S-epoxide and the
intermediary compounds can be prepared reliably, in high yields and
in high purity.
Inventors: |
Malik; Aslam A.; (Cameron
Park, CA) ; Clement; Todd E.; (Folsom, CA) ;
Palandoken; Hasan; (Bowling Green, KY) ; Robinson,
III; James; (Sacramento, CA) ; Stringer; Joy A.;
(Folsom, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Malik; Aslam A.
Clement; Todd E.
Palandoken; Hasan
Robinson, III; James
Stringer; Joy A. |
Cameron Park
Folsom
Bowling Green
Sacramento
Folsom |
CA
CA
KY
CA
CA |
US
US
US
US
US |
|
|
Assignee: |
Aerojet Fine Chemicals LLC
Sacramento
CA
|
Family ID: |
26830230 |
Appl. No.: |
13/490706 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13452582 |
Apr 20, 2012 |
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13490706 |
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|
11956515 |
Dec 14, 2007 |
8163933 |
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13452582 |
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|
11081106 |
Mar 14, 2005 |
7309803 |
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11956515 |
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10414541 |
Apr 14, 2003 |
6867311 |
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11081106 |
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09321645 |
May 28, 1999 |
6605732 |
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10414541 |
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60132278 |
May 3, 1999 |
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Current U.S.
Class: |
549/552 ;
560/29 |
Current CPC
Class: |
C07C 271/22 20130101;
C07C 213/00 20130101; C07C 213/00 20130101; C07B 2200/09 20130101;
C07D 303/36 20130101; C07D 263/20 20130101; C07C 215/08
20130101 |
Class at
Publication: |
549/552 ;
560/29 |
International
Class: |
C07C 271/22 20060101
C07C271/22; C07D 303/36 20060101 C07D303/36 |
Claims
1.-75. (canceled)
76. A composition comprising an R,S-halomethyl alcohol (R,S-HMA)
compound having the following general formula: ##STR00041## said
composition prepared by a method comprising: reducing a halomethyl
ketone (HMK) compound having the following general formula:
##STR00042## with a non-chelating, bulky reducing agent to form
said R,S-HMA compound; wherein: R.sup.1 is an amino acid side
chain; R.sup.2 is a blocking group; and X.sup.1 is a leaving
group.
77. The composition in accordance with claim 76, wherein said
non-chelating, bulky reducing agent used in said method is a member
selected from the group consisting of lithium aluminum
t-butoxyhydride (LATBH) and sodium tris-t-butoxyborohydride
(STBH).
78. The method in accordance with claim 77, wherein said
non-chelating, bulky reducing agent is lithium aluminum
t-butoxyhydride (LATBH).
79. The composition in accordance with claim 76, wherein R.sup.1 is
a member selected from the group consisting of a benzyl group, an
S-phenyl group, an alkyl group and para-nitrobenzene.
80. The composition in accordance with claim 76, wherein X.sup.1 is
a halogen.
81. The composition in accordance with claim 80, wherein X.sup.1 is
chloro or bromo.
82. The composition in accordance with claim 76, wherein R.sup.2 is
a blocking group selected from the group consisting of BOC, MOC and
CBZ.
83. The composition in accordance with claim 76, wherein the
reduction is carried out in a solvent selected from the group
consisting of diethyl ether, THF, MTBE, glyme and diglyme.
84. The composition in accordance with claim 83, wherein said
solvent is diethyl ether.
85. The composition in accordance with claim 76, wherein the
reduction is carried out at a temperature ranging from about
-30.degree. C. to about 25.degree. C.
86. The composition in accordance with claim 85, wherein the
reduction is carried out at a temperature ranging from about
-5.degree. C. to about 5.degree. C.
87. The composition in accordance with claim 76, wherein the
composition is a 8:1 mixture of R,S-HMA:S,S-HMA.
88. A composition comprising an R,S-halomethyl alcohol (R,S-HMA)
compound having the following general formula: ##STR00043## said
composition prepared by a method comprising: reducing a halomethyl
ketone (HMK) compound having the following general formula:
##STR00044## with a reducing agent selected from the group
consisting of sodium cyanoborohydride, cerium chloride/sodium
borohydride, K-Selectride.RTM., KS-Selectride.RTM. and (+)-Dip
Chloride.TM. to form said R,S-HMA compound; wherein: R.sup.1 is an
amino acid side chain; R.sup.2 is a blocking group; and X.sup.1 is
a leaving group.
89. The composition in accordance with claim 88, wherein the
composition is a 2:1 mixture of R,S-HMA:S,S-HMA.
90. An R,S-epoxide compound having the following general formula:
##STR00045## prepared by a method comprising: reducing a halomethyl
ketone (HMK) compound having the following general formula:
##STR00046## with a non-chelating, bulky reducing agent to form an
R,S-halomethyl alcohol (R,S-HMA) compound having the following
general formula: ##STR00047## and contacting said R,S-HMA compound
of Formula II with an alkali metal base to form said R,S-epoxide
compound; wherein: R.sup.1 is an amino acid side chain; R.sup.2 is
a blocking group; and X.sup.1 is a leaving group.
91. The compound in accordance with claim 90, wherein R.sup.1 is a
benzyl group; R.sup.2 is a BOC blocking group; and X.sup.1 is
chloro or bromo.
92. The compound in accordance with 88, wherein said non-chelating,
bulky reducing agent is a member selected from the group consisting
of lithium aluminum t-butoxyhydride (LATBH) and sodium
tris-t-butoxyborohydride (STBH).
93. The compound in accordance with claim 90, wherein the reduction
is carried out in diethyl ether.
94. The compound in accordance with claim 90, wherein said alkali
metal base is a member selected from the group consisting of NaOH,
KOH, LiOH, NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and KOtBu.
95. A composition comprising a mixture of R,S-halomethyl alcohol
(R,S-HMA) and S,S-halomethyl alcohol (S,S-HMA), wherein said
mixture is at least 2:1R,S-HMA:S,S-HMA.
96. The composition in accordance with claim 95, wherein said
mixture is about 8:1 R,S-HMA:S,S-HMA.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
13/452,582, filed Apr. 20, 2012, which is a division of application
Ser. No. 11/956,515, filed Dec. 14, 2007, which is a division of
application Ser. No. 11/081,106, filed Mar. 14, 2005 (now U.S. Pat.
No. 7,309,803, issued Dec. 18, 2007), which is a division of
application Ser. No. 10/414,541, filed Apr. 14, 2003 (now U.S. Pat.
No. 6,867,311, issued Mar. 15, 2005), which is a division of
application Ser. No. 09/321,645, filed May 25, 1999 (now U.S. Pat.
No. 6,605,732, issued Aug. 12, 2003), which claims the benefit of
U.S. Provisional Patent Application No. 60/132,278, filed May 3,
1999, which are incorporated herein by reference in their entirety
for all purposes.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH OR DEVELOPMENT
[0002] NOT APPLICABLE
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] Human immunodeficiency virus (HIV), the causative agent of
acquired immunodeficiency syndrome (AIDS), encodes three enzymes,
including the well-characterized proteinase belonging to the
aspartic proteinase family, the HIV protease. Inhibition of this
enzyme has been regarded as a promising approach for treating AIDS.
Hydroxyethylamine isosteres have been extensively utilized in the
synthesis of potent and selective HIV protease inhibitors. However,
this modern generation of HIV protease inhibitors has created an
interesting challenge for the synthetic organic chemist. Advanced
x-ray structural analysis has allowed for the design of molecules
that fit closely into active sites on enzymes creating very
effective drug molecules. Unfortunately, these molecules, designed
by molecular shape, are often difficult to produce using
conventional chemistry.
[0005] The modern generation of HIV inhibitors has structural
similarities in a central three-carbon piece containing two chiral
carbons that link two larger groups on each side (see, e.g., Parkes
et al., J. Org. Chem., 59:3656-3664 (1994). Numerous synthetic
routes to these isosteres have been developed. As illustrated
below, a common strategy to prepare the linking group starts with
an amino acid, such as phenylalanine, to set the chirality of the
first carbon. Then, the linking group is completed by a series of
reactions including a one-carbon homologization during which the
old amino acid carbon is transformed into a hydroxy-functionalized
carbon having the correct chirality. However, the commercial
production of isosteres by this method presents serious challenges,
generally requiring low-temperature organometallic reactions (Ghosh
et al., J. Org. Chem., 62:6080-6082 (1997) or the use of exotic
reagents.
##STR00001##
[0006] A second approach, which is illustrated below, is to convert
the amino acid to an aldehyde and to add the carbon by use of a
Wittig reaction to give an olefin (see, Luly et al., J. Org. Chem.,
52:1487-1492 (1987). The olefin is then epoxidized. Alternatively,
the aldehyde can be reacted with nitromethane, cyanide (see,
Shibata et al., Chem. Pharm. Bull., 46(4):733-735 (1998) or carbene
sources (see, Liu et al., Org. Proc. Res. Dev., 1:45-54 (1997).
Instability and difficulty in preparation of the aldehyde make
these routes undesirable (see, Beaulieu et al., J. Org. Chem.,
62:3440-3448 (1997).
##STR00002##
[0007] Other routes that have been published, but not
commercialized are illustrated in FIG. 1.
[0008] One of the best reagents that can be used to add a single
carbon to amino acids is diazomethane because it gives high yields
and few side-products. In addition, diazomethane reactions are very
clean, generating only nitrogen as a by-product. HIV inhibitor
molecules need high purity because of the high daily doses
required. As such, diazomethane is an ideal reagent for making high
purity compounds. In spite of the documented hazards of
diazomethane, processes have recently been developed that permit
the commercial scale use of diazomethane to convert amino acids to
the homologous chloromethyl ketones (see, U.S. Pat. No. 5,817,778,
which issued to Archibald et al. on Oct. 6, 1998; and U.S. Pat. No.
5,854,405, which issued to Archibald et al. on Dec. 29, 1998). FIG.
2 illustrates examples of HIV protease inhibitors wherein the
central linking group can be synthesized by the commercial use of
diazomethane. FIG. 3 illustrates a general reaction scheme that can
be used to prepare the S,S-epoxide compound using diazomethane.
[0009] The most useful amino acid isosteres are based on
phenylanaline. The key intermediate in the synthesis of
Sequinivir.RTM. (Roche) and Aprenavir.RTM. (Glaxo Wellcome) is the
(S,S--)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine Several
other protease inhibitors, such as those described in Chen et al.
(J. Med. Chem., 39:1991-2007 (1996) or those under development
(e.g., BMS-234475 or BMS-232623), use the diastereomeric
(R,S--)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine
[0010] Beginning with readily available (L)-phenylanaline, one is
able to manufacture
N-t-butoxycarbonyl-1-chloro-2-keto-4-phenylbutanamine (called
"chloroketone" or "CMK") using the methods described in the
literature (see, e.g., Parkes et al., J. Org. Chem., 59:3656-3664
(1994); Shaw, Methods in Enzymology, 11:677-686 (1967); and Dufour
et al., J. Chem. Soc. Perkin Trans. I, 1895-1899 (1986), the
teachings of which are incorporated herein by reference). However,
what are needed in the art are methods that allow one to produce
reliably and in high-yields either diastereomer, i.e., the S,S or
the R,S, from the common chloroketone starting material (see, FIG.
4). Quite surprisingly, the present invention fulfills this and
other needs.
BRIEF SUMMARY OF THE INVENTION
[0011] The present invention provides compounds and methods that
can be used to convert the intermediate halomethyl ketones (HMKs),
e.g., chloromethyl ketones, to the corresponding S,S- and
R,S-diastereomers. It is these chiral centers that determine the
chiral centers in the HIV protease inhibitor and, thus, the
efficacy of the drug. As explained herein, the present invention
provides (1) reduction methods; (2) inversion methods; and (3)
methods for preparing alkenes that, in turn, can undergo
epoxidation reactions to form the desired R,S-epoxide. Using the
various methods of the present invention, the R,S-epoxide and the
intermediary compounds can be prepared reliably, in high yields and
in high purity.
[0012] As such, in one embodiment, the present invention provides a
method for selectively preparing an R,S-halomethyl alcohol
(R,S-HMA) compound having the following general formula:
##STR00003##
the method comprising: reducing a compound having the following
general formula:
##STR00004##
with a nonchelating, bulky reducing agent to form the R,S-HMA
compound. In the above formulae, R.sup.1 is an amino acid side
chain (e.g., a benzyl group, an S-phenyl group, an alkyl group and
a para-nitrobenzene group, etc.); R.sup.2 is a blocking or
protecting group (e.g., Boc, Cbz, Moc, etc.); and X.sup.1 is a
leaving group (e.g., a halo group, such as chloro). In a presently
preferred embodiment, the nonchelating, bulky reducing agent is a
member selected from the group consisting of LATBH and STBH. In
another presently preferred embodiment, the reduction is carried
out in a solvent such as diethyl ether. Once formed, the R,S-HMA
can be reacted with an alkali metal base to form an
R,S-epoxide.
[0013] In another embodiment, the present invention provides a
method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound
having the following general formula:
##STR00005##
the method comprising: reducing a halomethyl ketone (HMK) compound
having the following general formula:
##STR00006##
with a reducing agent selected from the group consisting of sodium
cyanoborohydride, cerium chloride/sodium borohydride,
K-Selectride.RTM., KS-Selectride.RTM. and (+)-Dip Chloride.TM. to
form the R,S-HMA compound. In this method, R.sup.1 is an amino acid
side chain; R.sup.2 is a blocking group; and X.sup.1 is a leaving
group. Again, once formed, the R,S-HMA can be reacted with an
alkali metal base to form an R,S-epoxide.
[0014] In another aspect, the present invention provides inversion
methods that can be used to selectively prepare the R,S-epoxide. In
one embodiment of the inversion method, R,S-epoxide is prepared by
a four step process. More particularly, in one embodiment of the
inversion method, the present invention provides a method for
preparing an R,S-epoxide having the following general formula:
##STR00007##
the method comprising: (a) reducing a halomethyl ketone (HMK)
compound having the following general formula:
##STR00008##
with a reducing agent to form an S,S-halomethyl alcohol (S,S-HMA)
compound having the following general formula:
##STR00009##
(b) contacting the S,S-HMA compound of Formula II with a member
selected from the group consisting of arylsulfonyl halides and
alkylsulfonyl halides in the presence of an amine to form an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00010##
(c) contacting the S,S-HMS compound of Formula III with an acetate
in the presence of a phase transfer catalyst and water to form an
R,S-halomethyl acetate (R,S-HMAc) compound having the following
general formula:
##STR00011##
and (d) contacting the R,S-HMAc compound of Formula IV with an
alkali metal base to form the R,S-epoxide. In the above formulae,
R.sup.1 is an amino acid side chain (e.g., a benzyl group, an
S-phenyl group, an alkyl group, a para-nitrobenzene group, etc.);
R.sup.2 is a blocking or protecting group; X.sup.1 is a leaving
group (i.e., a halo group, such as chloro); R.sup.3 is a functional
group including, but not limited to, arylsulfonyls and
alkylsulfonyls (e.g., a mesyl group, a tosyl group, a triflate
group, a nosyl group, etc.); and R.sup.4 is an acyl group derived
from the acetate (e.g., an acetyl group).
[0015] In another embodiment of the inversion method, the present
invention provides a method for preparing an R,S-epoxide compound
having the following general formula:
##STR00012##
the method comprising: (a) contacting an S,S-halomethyl sulfonyl
(S,S-HMS) compound having the following general formula:
##STR00013##
with a carbamate-forming acetate to form a cyclic carbamate; and
(b) contacting the cyclic carbamate with an alkali metal base to
form the R,S-epoxide. In the above formulae, R.sup.1, R.sup.2,
R.sup.3 and X.sup.1 are as defined above. In a presently preferred
embodiment, the carbamate-forming acetate is sodium
trichloroacetate.
[0016] In yet another aspect, the present invention provides a
method for preparing R,S-epoxide by the epoxidation of an alkene.
More particularly, the present invention provides a method for
preparing an alkene having the following general formula:
##STR00014##
the method comprising: (a) contacting a compound having the
following general formula:
##STR00015##
with a hydrohalo acid to form a compound having the following
general formula:
##STR00016##
(b) reducing a compound of Formula II with a reducing agent to form
a compound having the following general formula:
##STR00017##
and (c) dehalohydroxylating a compound of Formula III to form the
alkene. In the above formulae, R.sup.1, R.sup.2, and X.sup.1 are as
defined above. Once prepared, the alkene can be converted to the
R,S-epoxide using, for example, m-chloroperbenzoic acid.
[0017] Other features, objects and advantages of the invention and
its preferred embodiments will become apparent from the detailed
description which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 illustrates various routes that can be used to
prepare an R,S-epoxide. FIG. 1(A) illustrates a method described by
Liu et al., Org. Proc. Res. Dev., 1:45-54 (1997); and Beaulieu et
al., J. Org. Chem., 62:3441 (1997). FIG. 1(B) illustrates a method
described by Parkes et al., J. Org. Chem., 59:3656-3664 (1994).
[0019] FIG. 2 illustrates examples of HIV protease inhibitors where
the central linking group can be synthesized by commercial use of
diazomethane.
[0020] FIG. 3 illustrates a general reaction scheme that can be
used to prepare the epoxide compound.
[0021] FIG. 4 illustrates the two diastereomers that can be formed
from the common chloroketone starting material, i.e., S,S-epoxide
and R,S-epoxide.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The present invention provides various compounds and methods
that can be used to prepare both reliable and in high yields either
diastereomer, i.e., the S,S-- or the R,S--, from the common
halomethyl ketone (e.g., chloromethyl ketone) starting material.
More particularly, as explained herein in greater detail, the
present invention provides (1) reduction methods; (2) inversion
methods, and (3) methods involving the epoxidation of alkenes.
A. The Reduction Methods
[0023] A variety of reducing agents can be used to reduce a
halomethyl ketone (HMK) to a halomethyl alcohol (HMA) (see, Table
I). However, under most conditions, the predominate diastereomer is
the 2S,3S-HMA. For instance, reduction of HMK with sodium
borohydride in ethanol (Chen et al., J. Med. Chem., 39:1991-2007
(1996) produces a 1:4 mixture of R,S:S,S HMA in near quantitative
yield. Moreover, the reduction of HMK with aluminium isopropoxide
in isopropanol can give ratios as high as 1:18 in favor of the
S,S-isomer (see, U.S. Pat. Nos. 5,684,176 and 5,847,144, both of
which issued to Hilpert). Thus, commercial routes to S,S-HMA are
easily achieved.
[0024] In contrast, the preparation of the R,S-isomer is much more
difficult. A slight increase in the R,S-HMA:S,S-HMA ratio is
achieved when the reaction solvent, ethanol, is replaced with THF.
Further enhancement in the R,S-HMA:S,S-HMA ratio is obtained when
the reduction is carried out in the presence of CeCl.sub.3
(Barluenga et al., J. Org. Chem., 62:5974 (1997); but even then the
ratio of R,S-HMA:S,S-HMA is <1:1. Other reducing agents, such as
LiAlH4, sodium cyanoborohydride, potassium borohydride, etc., under
a variety of reaction conditions, also fail to provide >1:1
R,S-HMA:S,S-HMA. In fact, a perusal of the literature supports the
observation that S,S-HMA is the preferred isomer using coordinating
reducing reagents, such as borohydrides or aluminium hydrides (see,
U.S. Pat. Nos. 5,684,176 and 5,847,144, both of which issued to
Hilpert).
[0025] In contrast to the teachings of both the scientific and
patent literature, it has now been discovered that the reduction of
HMK proceeds with high R,S diastereoselectivity when lithium
aluminum t-butoxyhydride (LATBH) is used as the reducing agent.
Quite surprisingly and in contrast to the findings of the prior
art, it has been found that the reduction of HMK with LATBH in, for
example, diethylether provides a 8:1 mixture of R,S-HMA:S,S-HMA in
97% yield. This high diastereofacial selectivity of the LATBH
reducing agent is unusual since reduction of HMK with similar
reducing agents, such as lithium aluminum hydride or sodium
borohydride, do not favor R,S diastereoselectivity (see, U.S. Pat.
Nos. 5,684,176 and 5,847,144, both of which issued to Hilpert).
TABLE-US-00001 TABLE 1 HMK Reductions: Sol- Reagent(s) vent(s)
Temp. Time R,S:S,S Li(OtBu).sub.3AlH Et.sub.2O 0.degree. C. 3 Hrs
.sup. 8:1 (+)-Dip Chloride .TM.(1.4eq) THF 5.degree. C.-RT 12 Hrs
.sup. 5:1 K-Selectride .RTM. THF Reflux 2 Hrs .sup. 2:1
K-Selectride .RTM./Ti(OiPr).sub.4 THF 25.degree. C. 30 Min .sup.
2:1 KS-Selectride .RTM. THF RT 2 Hrs .sup. 2:1
K-Select./MgBr.sub.2.cndot.OEt.sub.2 THF RT 30 Min 2.6:1 R-Alpine
Borane(Conc.) THF Reflux 9 Dys .sup. 1:1 L-Selectride .RTM. THF RT
1 Hr 0.9:1 NaBH.sub.4/CeCl.sub.3(anh.) THF RT 2 Hrs 0.8:1
N-Selectride .RTM. EtOH/ RT 2 Hrs 0.7:1 THF
NaBH.sub.4/CeCl.sub.3.cndot.7H.sub.2O THF 25.degree. C. 18 Hrs
0.7:1 NaBH.sub.4/EDTA(Na.sub.2.cndot.2H.sub.2O) THF RT 30 Min 0.7:1
NaCNBH.sub.3 THF RT 36 Hrs 0.7:1 (+)-2-Butanol/NaBH.sub.4 THF RT 1
Hr 0.6:1 Cp.sub.2TiBH.sub.4 Glyme RT 30 Min 0.6:1 NaBH.sub.4 THF
25.degree. C. 2 Hrs 0.6:1 NaBH.sub.4/(-)-2-Butanol THF RT 30 Min
0.6:1 NaBH.sub.4/Al(OiPr).sub.4 THF Reflux 2 Hrs 0.6:1
NaBH.sub.4/DiacetoneDglucose THF RT 12 Hrs 0.6:1 NaBH.sub.4/EDTA
THF RT 12 Hrs 0.6:1 NaBH.sub.4/L-Tartaric Acid THF 5.degree. C. 1
Hr 0.6:1 NaBH.sub.4/MgBr.sub.2.cndot.OEt.sub.2 THF RT 1 Hr 0.6:1
BHs-t-butylamine THF RT 1 Hr 0.5:1 LAH THF 25.degree. C. 1 Hr 0.5:1
LS-Selectride .RTM. THF RT 1 Hr 0.5:1 NaBH.sub.4/D-Tartaric Acid
THF RT 30 Min 0.5:1 (+)-2-Butanol.cndot.BH.sub.3 THF RT 1 Hr 0.4:1
NaBH.sub.4/CaCl.sub.2 MeOH RT 1 Hr 0.4:1 AminoAlcohol Borane THF
25.degree. C. 12 Hrs 0.3:1 Na(PEG).sub.2BH.sub.2 THF RT 30 Min
0.3:1 THF.cndot.BH.sub.3 EtOH/ RT 2 Hrs 0.2:1 THF Al(iOPr).sub.3
IPA 50.degree. C. 3 Dys 0.05:1 NaHB(OCH.sub.3).sub.3 MeOH RT 1 Hr
.sup. 1:1
[0026] As such, in one embodiment, the present invention provides a
method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound
having the following general formula:
##STR00018##
the method comprising: reducing a compound having the following
general formula:
##STR00019##
with a nonchelating, bulky reducing agent to form the R,S-HMA
compound.
[0027] In the above formulae, R.sup.1 is an amino acid side chain.
More particularly, in the above formulae, R.sup.1 is a side chain
from any of the naturally occurring amino acids or amino acid
mimetics. In a preferred embodiment, R.sup.1 is a benzyl group, a
substituted benzyl group, an S-phenyl group, an alkyl group or a
para-nitrobenzene group. In an even more preferred embodiment,
R.sup.1 is a benzyl group. R.sup.2, in the above formulae, is a
blocking or protecting group. It will be readily apparent to those
of skill in the art that suitable-amino blocking groups include,
for example, those known to be useful in the art of stepwise
synthesis of peptides. Included are acyl type protecting groups
(e.g., formyl, trifluoroacetyl, acetyl, etc.), aromatic urethane
type protecting groups (e.g., benzyloxycarboyl (Cbz), substituted
Cbz, etc.), aliphatic urethane type protecting groups (e.g.,
t-butyloxycarbonyl (Boc), isopropylcarbonyl, cyclohexyloxycarbonyl,
etc.) and alkyl type protecting groups (e.g., benzyl,
triphenylmethyl, etc.). In a presently preferred embodiment, the
blocking group is selected from the group consisting of Boc, Cbz
and Moc (methoxycarbonyl). In the above formulae, X.sup.1 is a
leaving group. Suitable leaving groups will be readily apparent to
those of skill in the art. In a presently preferred embodiment, the
leaving group is a halo group (e.g., Cl, Br, F or I). In an even
more preferred embodiment, X.sup.1 is a chloro or bromo group.
Although many of the compounds disclosed herein contain the
exemplar designation "halo," such as halomethyl ketone (HMK) or
halomethyl alcohol (HMA), it will be readily apparent to those of
skill in the art that other leaving groups can be used in place of
the halo group.
[0028] In the above embodiment, the reduction is carried out using
a nonchelating, bulky reducing agent. It has surprisingly been
discovered that nonchelating, bulky reducing agents favor the
S,R-diastereomer. Examples of nonchelating, bulky reducing agents
suitable for use in the methods of the present invention include,
but are not limited to, lithium aluminum t-butoxyhydride (LATBH),
sodium tris-t-butoxyborohydride (STBH). In a presently preferred
embodiment, the nonchelating, bulky reducing agent is LATBH. Once
formed, the R,S-HMA can be reacted with an alkali metal base to
form an R,S-epoxide. An exemplar embodiment of the above method is
illustrated by the following reaction scheme:
Synthesis of R,S-Boc-Epoxide by LATBH Reduction
##STR00020##
[0030] In this embodiment, the reduction is preferably carried out
in a solvent. It will be readily apparent to those of skill in the
art that numerous solvents can be used. Exemplar solvents include,
but are not limited, to the following: diethyl ether, THF, MTBE and
mixtures thereof Quite surprisingly, it has been found that the
reduction of LATBH is dependent on the solvent employed. For
instance, when diethyl ether is used as the solvent, a 8:1 mixture
of R,S-HMA:S,S-HMA is obtained. However, when THF or MTBE is used
as the solvent the ratio of R,S-HMA:S,S-HMA is less than or equal
to about 2:1. Based on these result, it is thought that a variety
of factors, such as steric, solvation and chelation, are
responsible for the high R,S diastereoselectivity observed in LATBH
reduction of HMK. Thus, when LATBH is used as the reducing agent,
diethyl ether is preferably used as the solvent.
[0031] LATBH is commercially available as a white powder and is
used as a suspension in diethyl ether. Alternately, LATBH can be
prepared in situ by the reaction of LAH with 3 equivalents of
t-butylalcohol in diethylether and then reacted with HMK. The best
solvent, as judged on basis of R,S-diastereoselectivity, is diethyl
ether. However, the solubility of HMK in diethyl ether is
relatively low and a large amount of diethyl ether is needed to
dissolve CMK, thereby reducing reactor efficiency to some extent.
The reactor efficiency can be improved by either adding HMK as a
solid or, alternatively, as a solution in a secondary solvent
(e.g., THF, toluene, ethyl acetate, etc.) to a suspension of LATBH
in diethyl ether. The reaction rate is not affected, but the
diastereoselectivity can be reduced from 8:1 in pure diethyl ether
to about 5:1 with the above modifications.
[0032] In this embodiment, the reduction can be carried out at a
temperature ranging from about -30.degree. C. to about 25.degree.
C. In a presently preferred embodiment, the reduction is carried
out at a temperature ranging from about -5.degree. C. to about
5.degree. C. At lower temperatures, larger amounts of solvent are
needed to maintain homogeneity; whereas at high temperatures,
formation of the epoxide, resulting from intramolecular
cyclization, is observed. At 0.degree. C., the reduction reaction
is rapid and is complete in less than about 30 minutes. It will be
readily apparent to those of skill in the art that the progress of
the reduction reaction can be monitored by, for example, HPLC, and
the reaction is deemed complete when the amount of unreacted HMK is
less than about 1%.
[0033] In another embodiment, the present invention provides a
method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound
having the following general formula:
##STR00021##
the method comprising: reducing a halomethyl ketone (HMK) compound
having the following general formula:
##STR00022##
with a reducing agent selected from the group consisting of sodium
cyanoborohydride, cerium chloride/sodium borohydride,
K-Selectride.RTM., i.e., potassium tri-sec-butylborohydride,
KS-Selectride.RTM., i.e., potassium trisamylborohydride, and
(+)-Dip Chloride.TM., i.e., (+)-B-chlorodiisopinocampheylborane, to
form the R,S-HMA compound. In this method, R.sup.1 is an amino acid
side chain; R.sup.2 is a blocking group; and X.sup.1 is a leaving
group. It will be readily apparent to those of skill in the art
that the foregoing discussions relating to R.sup.1, R.sup.2 and
X.sup.1 and their preferred embodiments are fully applicable to
this method and, thus, will not be repeated.
[0034] As with the previously described method, the reduction is
preferably carried out in a solvent. It will be readily apparent to
those of skill in the art that numerous solvents can be used.
Exemplar solvents include, but are not limited, to the following:
diethyl ether, THF, MTBE and mixtures thereof. In a preferred
embodiment, diethyl ether or THF is employed as the solvent.
Moreover, as with the previously described method, the reduction
can be carried out at a temperature ranging from about -30.degree.
C. to about 25.degree. C. In a presently preferred embodiment, the
reduction is carried out at a temperature ranging from about
-5.degree. C. to about 5.degree. C.
[0035] In yet another embodiment, the present invention provides a
method for isolating an R,S-halomethyl alcohol (R,S-HMA) from a
mixture of R,S-HMA and S,S-HMA. S,S-HMA is crystalline and is
relatively easy to purify. In contrast, the R,S-HMA is soluble in
most organic solvents and is difficult to purify by standard
purification techniques, such as recrystallization. Mixtures of
R,S-HMA and S,S-HMA can be separated by column chromatography or by
preparative scale HPLC, but are not practical economically.
[0036] It has now been discovered that a mixture of R,S-HMA and
S,S-HMA can be separated on the basis of differential solubility;
R,S-HMA is soluble in hot hexanes, whereas the crystalline
diastereomer, S,S-HMA, is not. As such, the present invention
provides a method for isolating an R,S-halomethyl alcohol (R,S-HMA)
from a mixture of R,S-HMA and S,S-HMA, the method comprising:
combining the mixture of R,S- and S,S-HMAs with hexane and heating
to a temperature ranging from 50.degree. C. to about 60.degree. C.
to produce a hexane extractant; cooling the hexane extractant to a
temperature ranging from about 0.degree. C. to about 10.degree. C.,
filtering the hexane extractant to form a first retentate and
recovering the first retentate; combining the first retentate with
hexane to form a hexane solution, heating the hexane solution to a
temperature ranging from about 50.degree. C. to about 60.degree.
C., and cooling the hexane solution to a temperature ranging from
about 30.degree. C. to about 40.degree. C. to produce a suspension;
and filtering the suspension to form a second retentate and
recovering the second retentate, wherein the R,S-HMA is present in
the second retentate.
[0037] For instance, a crude reaction mixture, consisting of 50-90%
R,S-HMA, 10-50% S,S-HMA and 0-10% Me-ester, was extracted with hot
hexane and the resulting hexane extractant was cooled to 10.degree.
C. and filtered to provide about 94% pure R,S-HMA in 74% yield
(based on HMK); the major contaminant was S,S-HMA (5%). Attempts to
purify the 94% pure material by differential solubility (above
treatment) or by recrystallization from a variety of
solvent/solvent mixtures were not completely successful. However,
it has been determined that the best way to purify the 94% pure
R,S-HMA is to dissolve it in hot hexane (about 60.degree. C.), cool
to about 40.degree. C., and then allowing the mixture to
crystallize at about 35.degree. C. to about 37.degree. C. for at
least 2 h. The crystallized product is then filtered at about
30.degree. C. to about 35.degree. C. to provide about 99.5% pure
R,S-HMA in 83% recovery. Interestingly, it has been found that if
the mixture is cooled to 25.degree. C. and filtered, a mixture
consisting of about 94.5% R,S-HMA and 5.5% S,S-HMA, is obtained.
This result is surprising because S,S-HMA is more crystalline and
is not soluble in hexane, thus suggesting that S,S-HMA, not
R,S-HMA, should be the first to crystallize. Although a variety of
solvent/solvent mixtures, such as methanol, methanol/water,
toluene, dibutyl ether, etc., have been used to purify 94% pure
R,S-HMA, the highest degree of purity/recovery is obtained with the
hot hexane method of the present invention.
[0038] Once prepared and purified, the R,S-HMA can be converted
into an R,S-epoxide. As such, in another embodiment, the present
invention provides an A method for preparing an R,S-epoxide
compound having the following general formula:
##STR00023##
the method comprising: reducing a haloketone (HMK) compound having
the following general formula:
##STR00024##
with a noncoordinating reducing agent to form an R,S-haloalcohol
(R,S-HMA) compound having the following general formula:
##STR00025##
and contacting the R,S-HMA compound of Formula II with an alkali
metal base to form the R,S-epoxide compound. It will be readily
apparent to those of skill in the art that the foregoing
discussions relating to R.sup.1, R.sup.2 and X.sup.1 and their
preferred embodiments are fully applicable to this method and,
thus, will not be repeated. In a presently preferred embodiment,
the noncoordination reducing agent is LATBH and the reduction is
carried out in diethyl ether. In another presently preferred
embodiment, the alkali metal base is selected from the group
consisting of NaOH, KOH, LiOH, NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and
KOtBu. In a further preferred embodiment, KOH is the alkali metal
base used. In another embodiment, calcium hydroxide can be
used.
B. The Inversion Method
[0039] In one embodiment of the inversion method, R,S-epoxide is
prepared by a four step process illustrated below. More
particularly, in one embodiment of the inversion method, the
present invention provides a method for preparing an R,S-epoxide
having the following general formula:
##STR00026##
the method comprising: (a) reducing a haloketone (HMK) compound
having the following general formula:
##STR00027##
with a reducing agent to form an S,S-haloalcohol (S,S-HMA) compound
having the following general formula:
##STR00028##
(b) contacting the S,S-HMA compound of Formula II with a member
selected from the group consisting of arylsulfonyl halides and
alkylsulfonyl halides in the presence of an amine to form an
S,S-halomethyl sulfonyl (S,S-HMS) compound having the following
general formula:
##STR00029##
(c) contacting the S,S-HMS compound of Formula III with an acetate
in the presence of a phase transfer catalyst and water to form an
R,S-halomethyl acetate (R,S-HMAc) compound having the following
general formula:
##STR00030##
and (d) contacting the R,S-HMAc compound of Formula IV with an
alkali metal base to form the R,S-epoxide. It will be readily
apparent to those of skill in the art that the foregoing
discussions relating to R.sup.1, R.sup.2 and X.sup.1 and their
preferred embodiments are fully applicable to this method and,
thus, will not be repeated. In the above formulae, R.sup.3 is a
functional group including, but not limited to, arylsulfonyls and
alkylsulfonyls. In a presently preferred embodiment, R.sup.3 is a
member selected from the group consisting of a methylsulfonyl group
(i.e., a mesyl group), a toluenesulfonyl group (i.e., a tosyl
group), a trifluoromethanesulfonyl group (i.e., a triflate group)
and a para-nitrobenzene sulfonyl group (i.e., a nosyl group). It
will be readily apparent to those of skill in the art that other
leaving groups can be used as R.sup.3 in place of the arylsulfonyl
and alkylsulfonyl groups. R.sup.4, in the above formulae, is an
acyl group derived from the acetate. In a presently preferred
embodiment, R.sup.4 is an acetyl group.
[0040] In the first step, i.e., step (a), a HMK is reduced with a
reducing agent to form an S,S-HMA. In a preferred embodiment, the
reducing agent is selected from the group consisting of sodium
borohydride, lithium aluminum hydride and sodium cyanoborohydride.
In another preferred embodiment, step (a) is carried out in a
solvent. Suitable solvents include, but are not limited to,
ethanol, methanol, isopropanol, THF, diethyl ether, etc. The
reduction can be carried out at a temperature ranging from about
-30.degree. C. to about room temperature and, more preferably, at
about -20.degree. C. In a presently preferred embodiment, the
reduction step is carried out using sodium borohydride in ethanol
to provide a 6:1 mixture of S,S-HMA:R,S-HMA in 98% yield. The
S,S-isomer is highly crystalline and can be easily purified by
recrystallization to provide >99.8% pure S,S-HMA in 80%
yield.
[0041] In addition to the foregoing, HMA can also be prepared by
Merwin Pondroff Verley reduction of HMK. In this process, HMK is
reacted with aluminum isopropoxide in refluxing IPA to give S,S-CMA
in high diastereoselectivity. Presumably, under these conditions,
the reduction occurs under chelation control and a mixture of
S,S-HMA:R,S-HMA with ratios as high as 20:1 is obtained (see, U.S.
Pat. Nos. 5,684,176 and 5,847,144, both of which issued to
Hilpert).
[0042] In the second step, i.e., step (b), an S,S-HMA is reacted
with an arylsulfonyl halide or an alkylsulfonyl halide in the
presence of an amine to form an S,S-halomethyl sulfonyl (S,S-HMS).
Suitable amines include, but are not limited to, trialkylamines
(e.g., trimethylamine, triethylamine, etc.), pyridine,
4-dimethylamino pyridine, etc. In a presently preferred embodiment,
the amine is triethylamine Step (b) can be carried out in a variety
of different solvents. Exemplar solvents include, but are not
limited to, the following: chlorinated solvents (e.g., methylene
chloride, dichloroethane, chlorotoluene, etc.), aromatic
hydrocarbons (e.g., toluene, xylenes, etc.), ethyl acetate, ethers
(e.g., THF, diethyl ether, etc.), etc. In another presently
preferred embodiment, step (b) is carried out at a temperature
ranging from about -30.degree. C. to about 100.degree. C. and, more
preferably, from about 10.degree. C. to about 70.degree. C.
[0043] In a particularly preferred embodiment of step (b), the
S,S-HMA is reacted with methanesulfonyl chloride in toluene in the
presence of an equivalent amount of triethylamine to give the
corresponding 2S,3S-CMA Mesylate in 98% yield. The reaction is
exothermic and is best conducted at a temperature ranging from
about from about 10.degree. C. to about 70.degree. C. The crude
mesylate is recrystallized from toluene to provide greater than 95%
pure S,S-CMA Mesylate in near quantitative yield. However, in the
preferred process, S,S-CMA Mesylate is not isolated and the
solution of crude S,S-CMA mesylate in toluene is used, without
purification, in the next step, i.e., step (c). Although this
mesylation step can be conducted in a variety of solvents, toluene
is the preferred solvent because it can be used in the next step,
thereby eliminating a solvent exchange step from the process.
[0044] In the third step, i.e., step (c), the S,S-HMS is reacted
with an acetate in the presence of a phase transfer catalyst and
water to from a HMAc. Suitable acetates for use in the present
method include, but are not limited to, the following: cesium
acetate, potassium acetate, tetrabutylammonium acetate and sodium
acetate. In a presently preferred embodiment, the acetate is cesium
acetate. A variety of phase transfer catalysts (PTCs) can be used
in carrying out step (c). Exemplar phase transfer catalysts
include, but are not limited to, crown ethers (e.g., 18-crown-6,
dibenzo crown ether, etc.), quaternary ammonium salts and
quaternary phosphonium salts (e.g., TATB, aliq. 336, etc.). In a
presently preferred embodiment, the phase transfer catalyst is a
crown ether. The crown ether 18-crown-6 is particularly preferred
because it allows for the production of R,S-HMAc with least amount
of side product. Moreover, the rate of reaction with 18-crown-6 is
much faster than with any of the other phase transfer catalysts. In
addition, 18-crown-6 can be easily removed from the product by a
simple water wash.
[0045] Step (c), i.e., the displacement reaction, can be carried
out in a variety of different solvents. Suitable solvents include,
but are not limited to, hydrocarbons (e.g., hexane, heptane, etc.),
aromatic hydrocarbons (e.g., toluene, xylene, benzene, etc.) and
chlorinated solvents (e.g., CCl.sub.4, dichloroethane,
chlorotoluenes, etc.). In a presently preferred embodiment, toluene
is used as the solvent because it can be used for both steps (b)
and (c), and it can be used as a crystallization solvent for the
R,S-HMAc. In addition, toluene is commercially available from a
variety of sources and can be recycled in high efficiency. The
displacement reaction, i.e., step (c) can be carried out at a
temperature ranging from about 20.degree. C. to about 100.degree.
C. In a presently preferred embodiment, the displacement reaction
is carried out at a temperature ranging from about 20.degree. C. to
about 100.degree. C.
[0046] In addition to the foregoing, it has been found that the
displacement reaction is dependent on the amount of water present
in the reaction mixture. Presumably, a small amount of water is
needed to overcome the lattice energy of the metal acetate, thereby
making the nucleophile accessible for the displacement reaction.
However, it has been found that increased amounts of water will
reduce the reactivity of the nucleophile by solvating it. Thus, in
a preferred embodiment, the water is maintained between about 0.5%
and about 10.0% and, more preferably, between about 0.5% and about
5%. Once the displacement reaction is completed, the crude product
can be isolated by crystallization from, for example,
toluene/heptane to give typically greater than 99.5% pure R,S-HMAc
in high yield. Alternately, the R,S-HMAc can be isolated and then
recrystallized from, for example, methanol/water to give pure
R,S-HMAc.
[0047] In the final step of the above method, i.e., step (d), the
R,S-HMAc is reacted with an alkali metal base to form the
R,S-epoxide. It has been found that hydrolysis of the R,S-HMAc
followed by subsequent intramolecular ring closure provides the
R,S-epoxide in near quantitative yield. In a presently preferred
embodiment, the alkali metal base is selected from the group
consisting of NaOH, KOH, LiOH, NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and
KOtBu. In another preferred embodiment, step (d) is carried out is
a solvent. Suitable solvents include, but are not limited to,
hydrocarbons, aromatic hydrocarbons, chlorinated solvents and
ethers (e.g., THF). In a presently preferred embodiment, the
solvent is a mixture of toluene and THF.
[0048] In a particularly preferred embodiment of step (d), the
R,S-HMAc is reacted with aqueous potassium hydroxide (KOH) in a
mixture of THF and ethanol. Evaporation of solvent followed by
tituration of the crude product with hexane afforded the desired
R,S-epoxide as a low melting, white solid.
[0049] Since the R,S-epoxide is soluble in most solvents, it is
difficult to purify. In addition, the R,S-epoxide is reactive
towards ring opening reactions and will react with potassium
hydroxide in ethanol to give the corresponding glycol or the
ethoxyglcyol side products. Using this method of the present
invention, high purity R,S-epoxide (>>99.5%) has been
prepared by incorporating the purity at the R,S-HMAc stage and then
maintaining the purity by minimizing side reactions in the final
step. Thus, it is important that the above conversion is achieved
in near quantitative yield and without formation of side products.
Again, in a preferred embodiment of this method, this is
accomplished by employing aqueous KOH. Presumably, in this form,
the hydroxide is nucleophilic enough to allow hydrolysis to occur,
but is not nucleophilic enough to react with the R,S-epoxide and
form side products.
[0050] Using this method of the present invention, greater than
99.5% pure R,S-epoxide can be prepared in 95-97% yields. The
R,S-epoxide prepared by this process can be characterized by NMR,
HPLC, TLC and DSC. Moreover, despite difficulties encountered in
the prior art relating to the purification of the R,S-epoxide, it
has now been discovered that the R,S-epoxide can be purified by
recrystallization from petroleum ether. This is an important
discovery because traditional purification techniques, such as
chromatography, are not applicable due to instability of the
R,S-epoxide towards silica gel and alumina. As such, in a preferred
embodiment, the above method further comprises: purifying the
R,S-epoxide by recrystallization with petroleum ether. An exemplar
embodiment of the above method is illustrated by the following
reaction scheme:
Preparation of the R,S-Epoxide Using One Embodiment of the
Inversion Method
##STR00031##
[0052] In another embodiment of the inversion method, the present
invention provides a method for preparing an R,S-epoxide compound
having the following general formula:
##STR00032##
the method comprising: (a) contacting an S,S-halomethyl sulfonyl
(S,S-HMS) compound having the following general formula:
##STR00033##
with a carbamate forming acetate to form a cyclic carbamate having
the following general formula:
##STR00034##
and (b) contacting the cyclic carbamate with an alkali metal base
to form the R,S-epoxide. It will be readily apparent to those of
skill in the art that the foregoing discussions relating to
R.sup.1, R.sup.2, R.sup.3 and X.sup.1 and their preferred
embodiments are fully applicable to this method and, thus, will not
be repeated. A "carbamate-forming acetate," as used herein, refers
to an acetate that contains a sufficient leaving group. Exemplar
carbamate-forming acetates include, but are not limited to, sodium
trichloroacetate, potassium trichloroacetate, tetrabutylammonium
trichloroacetate, sodium tribromoacetate, potassium tribromoacetate
sodium trifluoroacetate and potassium trifluoroacetate.
[0053] As with the previously described methods, step (a) can be
carried out in a variety of solvents, such as hydrocarbons (e.g.,
hexane, heptane, etc.), aromatic hydrocarbons (e.g., toluene,
xylene, benzene, etc.) and chlorinated solvents (e.g., CCl.sub.4,
dichloroethane, chlorotoluenes, etc.). In a preferred embodiment,
the solvent is toluene. In step (b) of the above method, the cyclic
carbamate is reacted with an alkali metal base to form the
R,S-epoxide. In a presently preferred embodiment, the alkali metal
base is selected from the group consisting of NaOH, KOH, LiOH,
NaOCH.sub.3, NaOCH.sub.2CH.sub.3 and KOtBu. In another preferred
embodiment, step (b) is carried out in a solvent. Suitable solvents
include, but are not limited to, hydrocarbons, aromatic
hydrocarbons, chlorinated solvents and ethers (e.g., THF). In a
presently preferred embodiment, the solvent is a mixture of THF and
ethanol.
[0054] In connection with the above method, the present invention
provides a cyclic carbamate compound having the following general
formula:
##STR00035##
[0055] In the above formula, R.sup.1 is an amino acid side chain
(e.g., benzyl); R.sup.2 is hydrogen or a blocking/protecting group
(e.g., BOC, MOC, CBZ, etc.); and X.sup.1 is a leaving group (e.g.,
a chloro or bromo group). This compound can be readily synthesized
and purified using the methods set forth in Example II.
C. The Alkene Method
[0056] In another embodiment, the present invention provides a
method for preparing an alkene having the following general
formula:
##STR00036##
the method comprising: (a) contacting a compound having the
following general formula:
##STR00037##
with a hydrohalo acid to form a compound having the following
general formula:
##STR00038##
(b) reducing a compound of Formula II with a reducing agent to form
a compound having the following general formula:
##STR00039##
and (c) dehalohydroxylating a compound of Formula III to form the
alkene. It will be readily apparent to those of skill in the art
that the foregoing discussions relating to R.sup.1, R.sup.2, and
X.sup.1 and their preferred embodiments are fully applicable to
this method and, thus, will not be repeated.
[0057] In step (a), a compound of Formula I is reacted with a
hydrohalo acid to form a compound of Formula II. Suitable hydrohalo
acids include, but are not limited to, hydrobromic acid,
hydrochloric acid and hydroiodic acid. In a presently preferred
embodiment, the hydrohalo acid is hydrobromic acid or hydrochloric
acid. Step (b) can be carried out using any of a variety of
reducing agents. In a presently preferred embodiment, sodium
borohydride is the reducing agent employed in step (b). Finally, in
step (c), compound III is dehalohydroxylated to form the desired
alkene. Suitable dehalohydroxylating compounds include, but are not
limited to, zinc (0) metals (e.g., zinc dust), nickel metals, zinc
mercury amalgan, etc. Step (c) can be carried out in a number of
different solvents. Suitable solvents include, but are not limited
to, methanol, ethanol, isopropanol, THF, MTBE, toluene, etc. In a
presently preferred embodiment, zinc dust in ethanol is used in
step (c).
[0058] Once prepared, the alkene can be converted to the
R,S-epoxide using, for example, m-chloroperbenzoic acid as
illustrated below.
[0059] In one particularly preferred embodiment of this method,
reaction of the diazoketone (i.e., the compound of Formula I),
which is prepared from phenylalanine using diazomethane, with
hydrobromic acid gives the bromoketone (i.e., the compound of
Formula II) in 77% yield. Reduction of the bromoketone with sodium
borohydride under conditions similar to those used for the
chloroketone gave high selectivity for the S,S-bromomethylalcohol
(i.e., the compound of Formula III) over the R,S-diastereomer. The
desired S,S-isomer was isolated in 85% yield after
recrystallization (see, Parkes et al., J. Org. Chem., 59:3656-3664
(1994).
[0060] The bromomethylalcohol was dehalohydroxylated to give the
olefin (i.e., the compound of Formula V) by zinc metal in ethanol.
Upon work up, the t-BOC protected S-3-amino-4-phenyl-1-butene was
isolated in 77% yield. Using this method of the present invention,
very pure material was prepared without the problems of
racemization associated with the reaction of the t-BOC protected
S-phenylalanal route. the alkene was converted to the R,S-epoxide
using, for example, a published route using m-chloroperbenzoic
acid. An exemplar embodiment of the above method is illustrated by
the following reaction scheme:
Preparation of the R,S-Expoxide Using the Alkene Method
##STR00040##
[0062] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters that can be changed or modified
to yield essentially the same results.
EXAMPLES
A. Example I
[0063] This example illustrates the preparation of S,S-CMA and
R,S-CMA using the reduction methods of the present invention.
[0064] 1. Preparation of S,S-CMA by Reduction
[0065] A 500 mL, 3-necked round bottom flask was fitted with a
condenser, thermocouple temperature probe, dry nitrogen inlet, and
magnetic stirring. A stirred solution of chloromethylketone (CMK)
(19.22 g, 0.0645 mol) and Isopropanol (200 mL) was heated to
50.degree. C. and aluminum isopropoxide (6.87 g, 0.0337 mol, 1.5
eq) was charged to the reactor. The reaction mixture was heated at
50.degree. C. for three hours at which point HPLC analysis
indicated 0.4% CMK remained. After heating for 1 additional hour
and cooling to room temperature, the reaction was quenched with
water (200 mL) and glacial acetic acid (.about.50 mL) to adjust the
pH to 4. The reaction was transferred to a separatory funnel and
the organic solids were extracted into ethyl acetate, resulting in
two clear phases. The phases were split and the organic phase was
evaporated to 18.63 g (97% yield) off-white solid.
S,S-Chloromethylalcohol (S,S-CMA): .sup.1H NMR (CDCl.sub.3):
.delta. 1.37 (s, 9H), 2.97 (m, 2H, J=5.1 Hz), 3.20 (br d, 1H),
3.55-3.69 (m, 2H), 3.83-3.93 (m, 2H), 4.59 (br d, 1H, J=6.6 Hz),
7.21-7.34 (m, 5H); HPLC (Short) t.sub.R 3.84 min=99.51%, 4.66
min=0.49%; HPLC (long) t.sub.R 13.26 min=99.50%, 17.42
min=0.50%.
[0066] Proton NMR analysis of final product indicated .about.37:1
ratio of S,S:R,S Boc-phenylalanine Chloromethylalcohol (CMA), and
traces of acetic acid. HPLC analysis indicated .about.32:1 ratio of
S,S:R,S CMA (95.1% S,S CMA, 3.0% R,S CMA, 0.6% CMK, and 1.3%
impurities from the starting material e.g. methyl ester,
boc-phenylalanine). Further purification was accomplished by
recrystallization from heptane.
[0067] 2. Sodium Cyanoborohydride Reduction of CMK
[0068] To a solution of sodium cyanaoborohydride (5.28 g, 84.0
mmol, 1.0 eq) in THF (25 mL) was added a solution of CMK (25.0 g,
84.0 mmol) in THF (100 mL), followed by addition of AcOH (10 mL)
over 0.5 h at RT. During this addition, internal temperature was
never allowed to rise above 42.degree. C. After 1.5 h, TLC analysis
of an aliquot indicated total consumption of CMK signaling reaction
completion. The reaction mixture was quenched with H.sub.2O (250
mL) and the resulting white slurry was stirred at ambient
temperature for 1 h. The mixture was extracted with ethyl acetate
(500 mL) and then concentrated on a rotary evaporator to a volume
of ca. 300 mL. Water (100 mL) and the remaining ethyl acetate was
removed under reduced pressure at 45.degree. C. The precipitated
product was filtered, washed with water (200 mL), and dried in a
vacuum oven at 45.degree. C./28 inch-Hg for 15 h to give 23.8 g
(95% yield) of a white solid. HPLC analysis revealed that the solid
contained a mixture of 41% R,S-CMA and 59% S,S-CMA.
[0069] 3. Preparation of R,S-CMA by Reduction with Cerium
Chloride/Sodium Borohydride
[0070] A 5000 mL, 3-necked round bottom flask was fitted with
mechanical stirring, Claisen head adapter, condenser, dry nitrogen
inlet, glass enclosed thermocouple temperature probe, and solids
addition funnel, all oven dried at 120.degree. C. and cooled under
dry nitrogen. To a stirred slurry of CMK (200 g, 0.672 mol, 1.0
eq), cerium chloride heptahydrate (250 g, 0.672 mol, 1.0 eq), and
THF (716 g) was added sodium borohydride (25.5 g, 0.673 mol, 1.0
eq) portionwise over 70 minutes during which time a 4.5.degree. C.
exotherm was observed. The reaction mixture was stirred for an
additional 5 hours at room temperature, at which time HPLC analysis
indicated that starting material had been consumed. The reaction
was cooled to 2.degree. C. and ethyl acetate (500 mL) was added.
The reaction was quenched with water (1000 mL) at a rate to control
the production of hydrogen gas and maintain at a temperature of
less than 20.degree. C. The pH of the reaction was adjusted to
approximately 6 with glacial acetic acid (18 mL) and additional
ethyl acetate (2500 mL) was added to dissolve the solids. The
reaction was warmed to room temperature and transferred to a 6000
mL separatory funnel The organic phase was separated, washed with
water and evaporated in vacuo to give 175 g (96% yield) of a white
solid. HPLC analysis of the solid indicated 36% R,S
boc-phenylalanine chloromethylalcohol (CMA) and 60% S,S CMA;
.sup.1H NMR analysis confirmed a 0.6:1 R,S:S,S CMA ratio.
[0071] 4. Preparation of R,S-CMA by Reduction with LATBH
[0072] Lithium tri-t-butoxyaluminohydride (LATBH) (93.87 g, 0.369
mol, 1.1 eq) and anhydrous diethyl ether (500 mL) were placed in a
reactor and cooled to 2.degree. C. A solution of CMK (99.84 g,
0.355 mol) and anhydrous diethyl ether (2000 mL) was added over 90
min maintaining an internal temperature of less than 5.degree. C.
After the addition was complete, the mixture was stirred for 30 min
at which point HPLC analysis indicated no starting material
remaining. The reaction was slowly quenched water (1500 mL) and
then acetified with glacial acetic acid (1000 mL) at a rate such
the temperature was below 10.degree. C. The reaction was warmed to
ambient and the organic phase was separated, washed with water and
was evaporated in vacuo to give an orange oil (100.12 g). Hexanes
(500 mL) was added to the flask and evaporated on the rotary
evaporator to remove residual t-butanol and isobutanol; the
evaporation yielded an orange oil/solid (97.34 g, 97% yield).
[0073] HPLC and .sup.1H NMR analysis indicated an approximately
6.5:1 ratio of R,S:S,S CMA. The R,S-isomers was purified by
extraction into refluxing hexanes (300 mL), filtration while hot to
remove the less soluble S,S-isomer, and slow cooling overnight.
After filtration and drying, 74.5 g (82.3% yield) of a product that
was 92.1% R,S CMA and 5.4% S,S CMA by HPLC and .sup.1H NMR
analysis.
[0074] 5. Purification of Mixtures of S,S- and R,S-CMA
[0075] CMA (170 g of a mixture of 0.6 to 1 isomers) and hexanes
(800 g) were charged to the flask and heated to reflux for 1 hour.
The less soluble isomer mix (90% S,S CMA, 9% R,S CMA) (99.6 g, 58%
yield) was removed by filtration of the hot mixture. The filtrate
was evaporated to 75% volume, cooled and filtered to give the more
soluble isomer mix (94% R,S CMA, 3% S,S CMA) 36.7 g (22% yield)
were removed by cold filtration through a 600 mL coarse, sintered
glass funnel The residual filtrate was dryed in vacuo to give a
yellow oil (18.6 g, 11% yield) containing a mixture of isomers.
[0076] A mixture of 32 g of the crude solid (93% R,S-CMA and 6%
S,S-CMA) from the hot hexane recrystallization and hexanes (600 mL)
was heated to 60.degree. C. The resulting solution was slowly
allowed to cool to 53.degree. C. and seeded with R,S-CMA crystals.
Further crystallization was observed at 37.degree. C. at which
point significant amount of white needles had formed in solution.
The internal temperature was maintained between 35-40.degree. C.
for 1.5 h, at which point the mixture was hot filtered to provide
25.7 g (80% recovery) of R,S-CMA as white needles. HPLC analyses
revealed that R,S-CMA was 99.8% pure and contained ca. 0.2%
S,S-CMA. Concentration of hexane filtrate on a rotary evaporator
afforded 6.1 g of a white solid which based on HPLC analysis was
found to be consist of 91.9% R,S-CMA and 6.4% S,S-CMA.
[0077] R,S-Chloromethylalcohol (R,S-CMA): .sup.1H NMR (CDCl.sub.3):
.delta. 1.36 (s, 9H), 2.94 (m, 2H, J=7.3 Hz), 3.54 (d, 2H, J=4.6
Hz), 3.77 (m, 1H, J=2.1 Hz), 3.94 (m, 1H, J=7.3 Hz), 4.99 (d, 1H,
J=8.8 Hz), 7.24 (br m, 5H); HPLC (Short) t.sub.R 3.87 min=0.21%,
4.69 min=99.79%.
B. Example II
[0078] This example illustrates the preparation of R,S,-Epoxide
using two different inversion methods. In NMR: Varian 300 MHz;
HPLC: Hewlett Packard 1100, column C18 reverse phase using
acetonitrile/water with phosphate buffer; melting points were
measured by DSC
[0079] 1. Preparation of R,S-Epoxide by the Inversion Route Via an
Acetate
[0080] a. Step 1: Mesylation
[0081] A 3 L jacketed reactor equipped with a mechanical stirrer,
addition funnel, reflux condenser, temperature probe, and a
nitrogen gas inlet was charged with S,S-CMA (150.3 g, 0.501 mol)
and toluene (1.5 L). The system was flushed with nitrogen and
triethylamine (62 g, 0.613 mol) was added. The resulting mixture
was treated, dropwise, with methanesulfonyl chloride (69 g, 0.595
mol). The rate of addition of methanesulfonyl chloride was
maintained so as to control the reaction temperature below
50.degree. C. When the addition was complete, the reaction mixture
was stirred for 1 h, sampled and analyzed by HPLC which indicated
that the reaction was complete. The reaction mixture was slowly
quenched into 10% aqueous potassium bicarbonate solution, and the
organic phase was separated and washed with water. The organic
layer containing the mesylate derivative was then dried
azeotropically and used without isolation in the displacement
reaction. In order to obtain yield/purity data, a sample of
reaction mixture was withdrawn and stripped off solvent under
reduced pressure to give S,S-CMA mesylate, a pale yellow solid: mp
117-121.degree. C.; .sup.1H NMR (CDCl.sub.3): .delta. 1.35 (s, 9H),
2.79 (br t, 1H, J=11.1 Hz), 3.04 (dd, 1H, J=14.4, 4.8 Hz), 3.17 (s,
3H), 3.73 (m, 2H, J=4.5 Hz), 4.15 (ddd, 1H, J=5.1, 4.8, 3.6 Hz),
4.69 (br d, 1H, J=6.6 Hz), 5.04 (br s, 1H), 7.20-7.34 (m, 5H); HPLC
revealed that the product was 99.7% (area %) pure.
[0082] b. Step 2: Displacement
[0083] A second reactor was charged with cesium acetate (241.7 g,
1.125 mol) and 18-crown-6 (33 g, 0.125 mol) in toluene (400 mL) and
the mixture was heated to 70 C. Next, a solution of S,S-CMA
mesylate in toluene was added over 1 h and the resulting mixture
was heated at 70.degree. C. for an additional 9 hrs at which time
TLC analysis indicated the reaction was complete. The reactor was
cooled to 35.degree. C., and water (1 L) was added. The organic
layer was separated and washed with water and the solvent was
evaporated until the concentration of the product was 20% by weight
as determined by 1 H NMR analysis. Heptane (1350 g) was added and
the mixture heated to 55.degree. C. for 30 min, and cooled to
ambient over 1 h. The mixture was then cooled to 5.degree. C.,
filtered, and the white solid was dried in vacuo to give 131.5 g
(77% yield) of
(2R,3S)--N-t-butoxycarbonyl-1-chloro-2-acetoxy-4-phenylbutanamine,
a white solid: mp 105-106.degree. C.; .sup.1H NMR (CDCl.sub.3):
.delta. 1.39 (s, 9H), 2.13 (s, 3H), 2.75 (br d, 2H, J=7.5 Hz), 3.56
(br d, 2H, J=6.3 Hz), 4.24 (ddd, 2H, J=7.4, 2.2 Hz), 4.52 and 4.67
(both br d, 1 H total, J=9.6 Hz), 5.03-5.12 (m, 1H, J=6.2, 2.1 Hz),
7.17-7.33 (m, 5H); TLC (silica gel, 30% EtOAc/Hexane):
R.sub.f=0.75; HPLC analysis revealed that the product was 99.7%
pure.
[0084] c. Step 3: Hydrolysis and Ring Closure
[0085] A 1 L flask fitted with a mechanical stirrer, addition
funnel, temperature probe, and a nitrogen inlet was charged with
R,S-CMA Acetate (34.3 g, 100 4 mmol), THF (156 mL), ethanol (90 mL)
and water (30 mL). The mixture was cooled to 0-3.degree. C. and a
43% aq. KOH solution (13.3 g of 86% potassium hydroxide dissolved
in 13.3 mL of water) was added dropwise to the reaction mixture so
as to maintain an internal temperature of <5.degree. C. The
reaction mixture was stirred at 0-3.degree. C. for 1.5 h and then
quenched with 6% aq. sodium biphosphate solution (250 mL); the
reaction temperature was maintained below 10.degree. C. during
quench. Diethyl ether (260 mL) was added and the organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered, and stripped of
solvent under reduced pressure to give a clear oil. Hexane (130 mL)
was added and the resulting mixture was concentrated on a rotary
evaporator till <10% hexane remained and the residue was seeded
with crystals of pure R,S-Epoxide. The mixture was then stored at
room temperature for 16 h and the precipitated solid was collected
by filtration and dried to provide 25.4 g (96%) of the title
compound, a white solid: mp (DSC): 51.56.degree. C.; .sup.1H NMR
(CDCl.sub.3): .delta. 1.39 (s, 9H), 2.59 (s, 1H), 2.70 (dd, 1H,
J=3.9 Hz), 2.91 (m, 2H, J=6.6 Hz), 3.01 (m, 1H, J=3.6 Hz), 4.13 (d,
1H, J=7.8 Hz), 4.49 (d, 1H, J=7.2 Hz), 7.27 (br m, 5H). The purity,
as determined by HPLC analysis, was 99.5%.
[0086] d. Alternate Process for Preparation of
2R,3S-Chloromethylacetate
[0087] A 4 L jacketed reactor equipped with a mechanical stirrer,
reflux condenser, temperature probe, and a nitrogen gas inlet was
charged with S,S-CMA Mesylate (246.5 g, 0.65 mol) and 18-crown-6
(43.4 g, 0.16 mol), cesium acetate (322.8 g, 1.685.7 mol) and
toluene (3.2 L). The resulting mixture was heated at 72.degree. C.
for 11 hours, at which point TLC analysis (silica gel, 30%
EtOAc/Hexane) indicated the starting material had been consumed.
The organic phase was separated and concentrated under reduced
pressure to provide a white solid. The residue was dissolved in
ethyl acetate (1.2 L) and the resulting solution was washed with
H.sub.2O (2.times.550 mL), dried (Na.sub.2SO.sub.4), filtered, and
stripped off solvent under reduced pressure to provide 216 g (97%)
of 92% pure R,S-CMA Acetate. Recrystallization of the crude product
from 85:15 methanol/water provided 99.7% pure R,S-CMA Acetate in
57% yield. The mother liquor was concentrated on rotary evaporator,
treated with water, and chilled to 5.degree. C. to provide an
additional 22 g of 98.2% pure product, thus increasing the total
yield of R,S-CMA Acetate to 76%.
[0088] 2. Preparation of R,S-Epoxide by the Inversion Route Via
Trichloroacetic Acid
[0089] a. Step 1: Preparation of `Cyclic Carbamate`
[0090] A 250 mL round-bottom flask equipped with a magnetic stir
bar, reflux condenser, temperature probe, and a nitrogen gas inlet
was charged with 9.98 g (26 4 mmol) of S,S-CMMs, 0.434 g (1.35
mmol) of tetrabutylammonium bromide (TBAB), 7.46 g (40.2 mmol) of
sodium trichloroacetate, and flushed vigorously with N.sub.2.
Toluene (104 mL, 90 g) was added under a steady stream of N.sub.2
and the resulting slurry was heated to .about.45.degree. C. The
reaction mixture was stirred at 45.degree. C. overnight, at which
point TLC analysis (silica gel, 30% EtOAc/Hexane) indicated the
starting material had been consumed. The toluene phase was
transferred from the reaction vessel into a 500 mL separatory
funnel and EtOAc/H2O (50 mL/100 mL), used to rinse the reactor, was
combined with the organic layer. After separating the two layers,
the organic layer was washed with H.sub.2O (1.times.100 mL), dried
over Na.sub.2SO.sub.4, filtered, and removed under vacuum. The
resulting crude solid was dried in a vacuum oven (45.degree. C.)
overnight to provide a yield of 92% (7.92 g, 24.3 mmol, .about.90%
pure).
[0091] This product was combined with the crude cyclic carbamate
(1.67 g, 5.13 mmol) from a previous small scale synthesis
(CP078-24) and crystallized from MeOH/H.sub.2O as follows: 9.59 g
of crude product was dissolved in 43 mL (34 g) of MeOH while
heating to 45.degree. C. To this warm MeOH solution was slowly
added 4 mL of H.sub.2O and the temperature allowed to reach ambient
without agitation. Needle formation was rapid and the flask was
cooled to 0-5.degree. C. prior to filtration, yielding 7.24 g
(75.5% recovery) of product (99.42% pure).
[0092] b. Step 2: Preparation of R,S-Epoxide
[0093] To a 50 mL round-bottom flask equipped with a magnetic stir
bar, temperature probe, and a nitrogen inlet was added a 43%
aqueous KOH solution (0.73 g soln., 5.82 mmol) and 1.0 g of
H.sub.2O. The contents of the flask were cooled to 0-3.degree. C.
with the aid of an ice-bath. A separate flask was charged with 0.99
g (2.22 mmol) of the `cyclic carbamate`, 3.2 g of THF, and 1.6 g of
EtOH and agitated to dissolve all solids. The `cyclic carbamate`
solution was added dropwise to the reaction flask via pipet so as
to maintain an internal temperature of <4.degree. C. Once
addition was complete, the reaction was stirred at 0-3.degree. C.
for .about.1 hour, at which point the reaction was quenched by
addition of a sodium biphosphate solution (0.448 g
NaH.sub.2PO.sub.4, 6.8 g H.sub.2O). The reaction quench was
conducted at such a rate as to keep the internal temperature
<10.degree. C. (Note: The reaction was analyzed for completion
via TLC after a 30 min. post-stir and found to contain the desired
epoxide.) The cloudy reaction mixture was diluted with 10 mL of
Et.sub.2O and the layers were separated. The clear organic layer
was dried over Na.sub.2SO.sub.4, filtered, and the solvent was
removed under vacuum to afford a clear oil (0.8 g).
[0094] The crude product was taken up in 20% EtOAc/hexanes (due to
solubility problems in desired eluent) and purified via column
chromatography (silica gel, 10% EtOAc/hexanes). R,S-epoxide, as
well as a small amount of a nonpolar impurity, were collected prior
to running a gradient to 50% EtOAc/hexanes to collect the deblocked
impurity. The two fractions were evaporated of solvent to obtain
clear oils: R,S-epoxide: 0.444 g (solidified under vacuum; HPLC:
.about.90%). The identity of the R,S-epoxide was confirmed by
.sup.1H NMR, HPLC, and TLC.
[0095] c. Mechanistic Discussion
[0096] Without intending to be bound by any theory, it is thought
that the reaction occurs through the following mechanism. Attack of
a trichloroacetate anion on the secondary mesylate in an SN.sub.2
fashion inverts the stereochemistry and provides the intermediate
R,S-chloromethyltrichloroacetate (R,S-CMAcCl.sub.3). Due to the
excellent leaving group ability of: CCl.sub.3 (trichlorocarbene),
nucleophilic attack of the carbamate nitrogen on the acetate
carbonyl and subsequent (or concurrent) loss of a proton provides
the cyclic carbamate. It is thought that treatment of this species
with aqueous base favors reaction of the hydroxide at the cyclic
carbonyl, possibly due to the added benefit of relieving the ring
strain of the molecule, resulting in the expected epoxide
(55-60%).
C. Example III
[0097] This example illustrates the preparation of the R,S-epoxide
by the epoxidation of an alkene.
[0098] 1. Preparation of Bromomethyl Ketone (BMK)
[0099] A solution of diazomethyl ketone (DMK) in ethyl
acetate/diethyl ether (16.8 g solution, 1 g DMK, 3.5 mmol) was
cooled to 5.degree. C. and treated dropwise with a solution of
hydrobromic acid (1.8 g, 10.6 mmol); the reaction temperature was
maintained below 10.degree. C. during the addition. The resulting
mixture was stirred at 0-5.degree. C. for 2 hours and quenched with
water (20 mL). The organic layer was separated and washed with
water (3.times.20 mL) until the pH of the final water wash was
>6. The organic layer was concentrated on a rotary evaporator to
give 0.92 g (77%) of an off-white solid. The product purity, as
determined by HPLC, was 91% . .sup.1H NMR.sup.-(S,S-BMK;
CDCl.sub.3)): .delta. 1.41 (s, 9H), 3.07 (m, 2H, J=6.6 Hz), 3.94
(m, 2H, J=16.2 Hz), 4.72 (q, 1H, J=7.2 Hz), 5.07 (d, 1H, J=7.5 Hz),
7.20-7.31 (br m, 5H).
[0100] 2. Preparation of Bromomethylalcohol (BMA)
[0101] A mixture of bromomethylketone (20.3 g, 59.3 mmol), ethyl
acetate (160 mL), and ethanol (240 mL) was cooled to -30.degree. C.
and treated, dropwise, with a slurry of sodium borohydride (1.16 g,
30.7 mmol) in ethanol (80 mL). The reaction mixture was stirred at
-30.degree. C. for 30 min. and quenched with acetic acid (4 mL);
the reaction temperature was maintained below -20.degree. C. during
the quench. The reaction mixture was then warmed to room
temperature and treated with water (100 mL) and ethyl acetate (150
mL). The layers were separated and the organic layer was filtered
to give 2.8 g of 96.6% pure S,S-BMA. The organic layer was then
dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo to give
14.2 g of a mixture consisting of 85% S,S-BMA, 6% R,S-BMA, and 5%
methyl ester. .sup.1H NMR (S,S-BMA; CDCl.sub.3): .delta. 1.36 (s,
9H), 2.98 (br m, 2H, J=4.5 Hz), 3.46 (br m, 1H, J=9 Hz), 3.54 (br
m, 1H), 3.86 (br s, 2H), 4.56 (br s, 1H), 7.20-7.31 (m, 5H); HPLC
(Short) t.sub.R 2.29 min=0.07%, 3.88 min=2.68%, 4.29 min=96.61%,
5.25 min=0.64%.
[0102] 3. Preparation of BOC-Alkene:
[0103] A mixture of crude BMA (12.1 g, 35.2 mmol) prepared above
and ethanol (240 mL) was heated to reflux and zinc dust (22.4 g,
343 mmol) was added. The resulting mixture was refluxed for 5 h, at
which time TLC analysis (silica gel, 30% EtOAc/Hexane) indicated
the starting material had been consumed. The reaction mixture was
cooled to room temperature, unreacted zinc dust was removed by
filtration, and the filtrate was concentrated in vacuo to give an
oil. This oil was dissolved in ethyl acetate (100 mL) and washed
with 2% aqueous acetic acid (50 mL). The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and evaporated to
give 7.5 g of crude product, an oil; this oil solidified on
standing at room temperature to give a white solid. The solid was
dissolved in methylene chloride (50 mL) and the solution was
filtered through 10 g of silica gel. Evaporation of the solvent
gave 6.0 g (77% yield of the desired olefin. HPLC analysis showed
the olefin was >99% pure. BOC-Alkene: .sup.1H NMR (CDCl.sub.3):
.delta. 1.40 (s, 9H), 2.83 (br d, 2H, J=6.6 Hz), 4.43 (br s, 2H),
4.56 (br s, 2H), 5.06-5.13 (m, 2H, J=17.4, 10.5, 1.2 Hz), 5.8 (ddd,
2H, J=17.1, 10.5, 5.4 Hz), 7.20-7.31 (m, 5H); IR (thin film): v
3359 (NH), 1686 (CO), 1645 (alkene); HPLC (Short) t.sub.R 3.87
min=0.65%, 4.01 min=0.04%, 4.69 min=0.19%, 8.38 min=99.12%; MS, m/e
MH.sup.| 248.1661.
[0104] 4. R,S-Epoxide by Alkene route
[0105] A mixture of BOC-alkene (0.498 g, 2.02 mmol),
meta-chloroperbenzoic acid (1.93 g, 8.1 mmol) and dichloromethane
(22 mL) was stirred at ambient temperature for 3 h at which time
HPLC analysis indicated the starting material had been consumed.
The reaction mixture was quenched with aqueous 10% Na.sub.2SO.sub.3
(60 mL), and diluted with diethyl ether. The organic layer was
washed with cold saturated Na.sub.2CO.sub.3 (60 mL), brine (60 mL),
dried over Na.sub.2SO.sub.4, and the solvent evaporated to provide
a clear oil that solidified on standing. A white solid (0.49 g,
1.86 mmol) was isolated in 92% yield and was shown to be a 5.2:1
mixture of R,S- and S,S-epoxide, respectively (HPLC, 96.5% pure
combined). Analysis of the product mixture by proton NMR
spectroscopy indicated an approximate 5.7:1 ratio of diasteriomeric
epoxides and no alkene starting material.
[0106] It is to be understood that the above description is
intended to be illustrative and not restrictive. Many embodiments
will be apparent to those of skill in the art upon reading the
above description. The scope of the invention should, therefore, be
determined not with reference to the above description, but should
instead be determined with reference to the appended claims, along
with the full scope of equivalents to which such claims are
entitled. The disclosures of all articles and references, including
patent applications and publications, are incorporated herein by
reference for all purposes.
* * * * *