U.S. patent application number 13/435720 was filed with the patent office on 2012-08-02 for treprostinil production.
This patent application is currently assigned to United Therapeutics Corporation. Invention is credited to Hitesh BATRA, Raju PENMASTA, Vijay SHARMA, Sudersan M. TULADHAR, David A. WALSH.
Application Number | 20120197041 13/435720 |
Document ID | / |
Family ID | 45067076 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120197041 |
Kind Code |
A1 |
BATRA; Hitesh ; et
al. |
August 2, 2012 |
TREPROSTINIL PRODUCTION
Abstract
The present invention is directed to a novel method for
preparing a synthetic intermediates for treprostinil. Also
described are methods of preparing treprostinil comprising
utilizing novel intermediates described herein as well as novel
intermediates useful for synthesis prostacyclin derivatives, such
as treprostinil.
Inventors: |
BATRA; Hitesh; (Herndon,
VA) ; PENMASTA; Raju; (Ashburn, VA) ; SHARMA;
Vijay; (Olney, MD) ; TULADHAR; Sudersan M.;
(Silver Spring, MD) ; WALSH; David A.;
(Spotsylvania, VA) |
Assignee: |
United Therapeutics
Corporation
|
Family ID: |
45067076 |
Appl. No.: |
13/435720 |
Filed: |
March 30, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13151465 |
Jun 2, 2011 |
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13435720 |
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61351115 |
Jun 3, 2010 |
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Current U.S.
Class: |
562/466 ;
568/311; 568/442; 568/654 |
Current CPC
Class: |
C07C 67/343 20130101;
C07C 29/42 20130101; C07B 2200/07 20130101; C07F 7/1892 20130101;
C07C 51/00 20130101; C07C 59/72 20130101; Y02P 20/55 20151101; C07C
29/143 20130101; C07C 51/367 20130101; C07C 51/367 20130101; C07C
51/09 20130101; C07C 253/30 20130101; C07C 45/29 20130101; C07C
45/64 20130101; C07C 255/13 20130101; C07C 69/736 20130101; C07C
59/72 20130101; C07C 45/61 20130101; C07C 59/72 20130101; C07C
67/343 20130101; C07C 45/00 20130101; C07C 253/30 20130101; C07C
51/09 20130101 |
Class at
Publication: |
562/466 ;
568/311; 568/442; 568/654 |
International
Class: |
C07C 65/26 20060101
C07C065/26; C07C 47/575 20060101 C07C047/575; C07C 43/23 20060101
C07C043/23; C07C 45/49 20060101 C07C045/49 |
Claims
1. A process of preparing a substituted tricyclic enone compound
useful in preparing treprostinil, the enone compound corresponding
to formula: ##STR00066## wherein R is p-methoxybenzyl; and P.sub.1,
for each occurrence is independently an alcohol protecting group,
which includes a step of subjecting an alkene-substituted,
alkyne-substituted benzene corresponding to the formula:
##STR00067## wherein R and P.sub.1 are defined above, to
intramolecular cyclization with carbon monoxide.
2. The process of claim 1 wherein the carbon monoxide for
intramolecular cyclization is used in the form of a cobalt-carbon
monoxide complex.
3. The process of claim 2 wherein the alkene-substituted,
alkyne-substituted benzene compound corresponding to the formula:
##STR00068## is prepared by reacting an alkene-substituted
benzaldehyde corresponding to the formula: ##STR00069## with a
substituted 1,2-alkyne corresponding to the formula: ##STR00070##
wherein R and P.sub.1 are defined in claim 1.
4. The process of claim 3 wherein the alkene-substituted
benzaldehyde is prepared by modified Claisen rearrangement of an
O-allyl-substituted benzaldehyde of formula: ##STR00071## followed
by protection of the resultant meta-phenolic group with a
p-methoxybenzyl group.
5. A process of preparing treprostinil or a pharmaceutically
acceptable salt thereof, of the formula: ##STR00072## or
pharmaceutically acceptable salts thereof, which comprises: (a)
derivatizing m-hydroxybenzaldehyde with an allyl halide, to form an
oxyalkene-substituted benzaldehyde of formula: ##STR00073## (b)
subjecting the substituted oxyalkene-substituted benzaldehyde to
Claisen rearrangement to form the m-hydroxy-substituted
benzaldehyde of formula: ##STR00074## (c) protecting the
m-hydroxy-substituted benzaldehyde with a p-methoxybenzyl, to form
a protected benzaldehyde of formula: ##STR00075## wherein R is
p-methoxybenzyl (d) reacting the protected benzaldehyde with a
5-oxy-substituted decan-1,2-yne of formula: ##STR00076## wherein
P.sub.1 is an alcohol protecting group, to yield the compound of
formula: ##STR00077## wherein R and P.sub.1 are defined above; (e)
oxidizing the resulting compound to a ketone compound of:
##STR00078## wherein R and P.sub.1 are defined above; (f) chirally
reducing the ketone compound to a chiral alcohol compound of
formula: ##STR00079## wherein R and P.sub.1 are defined above; (g)
protecting the chiral alcohol compound to yield a compound of
formula: ##STR00080## wherein R is defined above, and P.sub.1, for
each occurrence is independently an alcohol protecting group; (h)
intra-molecularly cyclizing the resulting compound to obtain a
tricyclic enone compound of formula: ##STR00081## wherein R is
defined above, and P.sub.1, for each occurrence is independently an
alcohol protecting group; (i) converting the tricyclic enone to a
tricyclic hydroxyl compound of formula: ##STR00082## (j) alkylating
the tricyclic hydroxyl compound to yield an alkylated compound of
formula: ##STR00083## wherein Z a nitrile or CH.sub.2COOR.sub.1
group, wherein R.sub.1 is an alkyl group; and (k) hydrolizing the
alkylated compound to treprostinil, followed by optional conversion
to a pharmaceutically acceptable salt thereof.
6. The process of claim 5 including the additional, final step of
converting the treprostinil so formed to its sodium salt.
7. A substituted tricyclic enone compound useful in the synthesis
pharmaceutically active prostacyclin derivatives, corresponding to
the formula: ##STR00084## wherein R is p-methoxybenzyl; and
P.sub.1, for each occurrence is independently an alcohol protecting
group.
8. A substituted compound of formula: ##STR00085## wherein:
##STR00086## X is COH or R' is P.sub.1 or --H; and P.sub.1, for
each occurrence is independently an alcohol protecting group.
9. A compound of claim 8, of the formula: ##STR00087##
10. A compound of claim 8, of the formula: ##STR00088## wherein R
is p-methoxybenzyl; and P.sub.1 is an alcohol protecting group.
11. A compound of claim 8, of the formula: ##STR00089## wherein R
is p-methoxybenzyl; and P.sub.1 for each occurrence is
independently an alcohol protecting group.
Description
[0001] The present application is a Continuation of U.S.
application Ser. No. 13/151,465, filed Jun. 2, 2011, which claims
the benefit of U.S. provisional application No. 61/351,115 filed
Jun. 3, 2010, which are incorporated herein by reference in their
entirety.
[0002] The present application relates to a process for producing
prostacyclin derivatives, such as Treprostinil, and novel
intermediate compounds useful in the process.
[0003] (+)-Treprostinil (also known as UT-15) is the active
ingredient in Remodulin.RTM., a commercial drug approved by FDA for
the treatment of pulmonary arterial hypertension (PAH). It was
first described in U.S. Pat. No. 4,306,075. Treprostinil is a
stable analog of prostacyclin (PGI.sub.2) belonging to a class of
compounds known as benzindene prostacyclins, which are useful
pharmaceutical compounds possessing activities such as platelet
aggregation inhibition, gastric secretion reduction, lesion
inhibition, and bronchodilation.
##STR00001##
[0004] U.S. Pat. No. 5,153,222 describes use of treprostinil for
treatment of pulmonary hypertension. Treprostinil is approved for
the intravenous as well as subcutaneous route, the latter avoiding
potential septic events associated with continuous intravenous
catheters. U.S. Pat. Nos. 6,521,212 and 6,756,033 describe
administration of treprostinil by inhalation for treatment of
pulmonary hypertension, peripheral vascular disease and other
diseases and conditions. U.S. Pat. No. 6,803,386 discloses
administration of treprostinil for treating cancer such lung,
liver, brain, pancreatic, kidney, prostate, breast, colon and
head-neck cancer. U.S. patent application publication No.
2005/0165111 discloses treprostinil treatment of ischemic lesions.
U.S. Pat. No. 7,199,157 discloses that treprostinil treatment
improves kidney functions. U.S. Pat. No. 7,879,909 discloses
treprostinil treatment of neuropathic foot ulcers. U.S. publication
No. 2008/0280986 discloses treprostinil treatment of pulmonary
fibrosis, interstitial lung disease with treprostinil and asthma.
U.S. Pat. No. 6,054,486 discloses treatment of peripheral vascular
disease with treprostinil. U.S. patent application publication No.
2009/0036465 discloses combination therapies comprising
treprostinil. U.S. publication No. 2008/0200449 discloses delivery
of treprostinil using a metered dose inhaler. U.S. Pat. Nos.
7,417,070, 7,384,978 and 7,544,713 as well as U.S. publications
Nos. 2007/0078095, 2005/0282901, and 2008/0249167 describe oral
formulations of treprostinil and other prostacyclin analogs as well
as their use for treatment of a variety of conditions. U.S.
provisional application No. 61/354,949 filed Jun. 15, 2010
discloses the use of orally administered treprostinil for treatment
of Raynaud's phenomenon, systemic sclerosis and digital ischemic
lesions.
[0005] Treprostinil and other prostacyclin derivatives have been
prepared as described in Moriarty, et al in J. Org. Chem. 2004, 69,
1890-1902, Drug of the Future, 2001, 26(4), 364-374, U.S. Pat. Nos.
4,306,075, 6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223
and US Publication No. 2009/0163738. The entire teaching of these
documents are incorporated herein by reference in their entirety.
The methods described in these patent documents, however, do not
describe a feasible production method for producing
stereochemically pure treprostinil because, for example, the
methods require the use of expensive reagents and tedious
chromatographic purification techniques. Therefore, there is a need
in the art for an economical, efficient and simplified method for
preparing treprostinil and its synthetic intermediates.
SUMMARY
[0006] One embodiment relates to a method of preparing a synthetic
intermediate of treprostinil represented by the following
structural formula:
##STR00002##
[0007] wherein:
[0008] R is --(CH.sub.2).sub.nX or P.sub.1;
[0009] X is H, phenyl, --CN, --OR.sub.1 or COOR.sub.1;
[0010] R.sub.1 is an alkyl, THP or TBDMS;
[0011] P.sub.1, for each occurrence, is independently an alcohol
protecting group;
[0012] R.sub.2 and R.sub.3 are each independently --H or an
alkyl;
[0013] Z is --H, cycloalkyl or phenoxy (i.e. --O-phenyl);
[0014] n is 0, 1, 2 or 3; and
[0015] p is 1, 2, 3, 4 or 5.
[0016] The method comprises the step of reacting an aldehyde
compound represented by structural formula (I):
##STR00003##
[0017] with an alkyne compound represented by structural formula
(a):
##STR00004##
wherein R, P.sub.1, R.sub.1, R.sub.2, R.sub.3, X, Z, n and p are as
described above for structural formula (A).
[0018] Another embodiment is directed to a method of preparing a
prostacyclin derivative (e.g., treprostinil) comprising reaction 1,
and optionally comprising one or more reaction steps 2-9 according
to Scheme 2.
[0019] Yet another embodiment relates to a method of preparing a
synthetic intermediate of treprostinil represented by the following
structural formula:
##STR00005##
[0020] wherein:
[0021] P.sub.1 is an alcohol protecting group;
[0022] R is --(CH.sub.2).sub.nX;
[0023] X is H, phenyl, --CN, --OR.sub.1 or COOR.sub.1;
[0024] R.sub.1 is an alkyl, THP or TBDMS; and
[0025] n is 1, 2 or 3.
[0026] The method comprises reacting a compound represented by
structural formula (I):
##STR00006##
with a compound represented by structural formula (a):
##STR00007##
wherein R and P.sub.1 are as described above for structural formula
(A).
[0027] Another embodiment is to a method of preparing treprostinil
comprising reaction 1, and optionally comprising one or more
reactions 2-9 according to Scheme 2.
[0028] Yet another embodiment is a compound of formula (1):
##STR00008##
[0029] wherein: [0030] R is (CH.sub.2).sub.mCO.sub.2R.sub.1, [0031]
m is 1, 2 or 3, and [0032] R.sub.1 is an alkyl group, THP, TBDMS or
a substituted or unsubstituted benzyl group.
[0033] And yet another embodiment is a compound represented by
structural formula (A):
##STR00009##
[0034] wherein: [0035] P.sub.1 is an alcohol protecting group;
[0036] wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or
3, and [0037] R.sub.1 is an alkyl group or a substituted or
unsubstituted benzyl group.
[0038] And yet another embodiment is a compound represented by
structural formula (4):
##STR00010##
wherein:
[0039] each of P.sub.1 and P.sub.2 is an alcohol protecting
group;
[0040] wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or
3, and
[0041] R.sub.1 is an alkyl group, or a substituted or unsubstituted
benzyl group.
[0042] And yet another embodiment is a compound represented by
structural formula (5):
##STR00011##
wherein:
[0043] each of P.sub.1 and P.sub.2 is an alcohol protecting
group;
[0044] wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or
3, and
[0045] R.sub.1 is an alkyl group, or a substituted or unsubstituted
benzyl group.
[0046] And yet another embodiment is a compound represented by
structural formula (6):
##STR00012##
wherein:
[0047] P.sub.1 is an alcohol protecting group;
[0048] wherein m is 1, 2 or 3, and
[0049] R.sub.1 is an alkyl group, or hydrogen.
DETAILED DESCRIPTION
[0050] Unless otherwise specified, "a" or "an" means "one or
more".
[0051] The present application is directed to methods of preparing
treprostinil and synthetic intermediates useful of synthesizing
treprostinil as well to synthetic intermediates themselves. The
present application is also directed to methods of preparing
treprostinil or a pharmaceutically acceptable salt thereof
comprising the alkyne addition reaction described herein. Preferred
treprostinil salts may include the sodium salt and the
diethanolamine salt (see, e.g., U.S. Pat. No. 7,417,070).
[0052] In some embodiments, the present application is directed to
a method of preparing a synthetic intermediate (A) of treprostinil
through a stereoselective alkyne addition reaction.
[0053] One embodiment is directed to a novel method (reaction 1)
for preparing a compound of structural formula (A) comprising the
step of reacting an aldehyde of structural formula (I) with an
alkyne of structural formula (a):
##STR00013##
wherein R, P.sub.1, R.sub.1, R.sub.2, R.sub.3, X, Z, n and p are as
described above for structural formula (A').
[0054] Another embodiment is directed to a novel method (reaction
1) for preparing a compound of structural formula (A) comprising
the step of reacting an aldehyde of structural formula (I) with an
alkyne of structural formula (a):
##STR00014##
wherein: [0055] P.sub.1 is an alcohol protecting group; [0056] R is
--(CH.sub.2).sub.nX; [0057] X is H, phenyl, --CN, --OR.sub.1 or
COOR.sub.1; [0058] R.sub.1 is an alkyl, THP, TBDMS or a substituted
or unsubstituted benzyl group; and [0059] n is 1, 2 or 3.
[0060] As used herein, "an alcohol protecting group" is a
functional group that protects the alcohol group from participating
in reactions that are occurring in other parts of the molecule.
Suitable alcohol protecting groups are well known to those of
ordinary skill in the art and include those found in T. W. Greene,
Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc.
1981, the entire teachings of which are incorporated herein by
reference. Exemplary alcohol protecting groups include, but are not
limited to, actetyl, benzoyl, benzyl, p-methoxyethoxymethyl ether,
methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether,
trityl, silyl ether (e.g., trimethylsilyl (TMS),
tert-butyldimethylsilyl (TBMDS), tert-butyldimethylsilyloxymethyl
(TOM) or triisopropylsilyl (TIPS ether), tetrahydropyranyl (THP),
methyl ether and ethoxyethyl ether (EE).
[0061] An alkyl group may be a saturated straight-chain or branched
aliphatic group. For example, an alkyl group may a (C1-C6)alkyl,
(C1-C5)alkyl, (C1-C4)alkyl or (C1-C3)alkyl. Examples of alkyl
groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl. An
alkyl group is optionally substituted with an alkyl, a cycloalkyl
(e.g., cyclopentyl or cyclohexyl), an aryl (e.g., phenyl), or
heteroaryl group.
[0062] A phenyl group may be optionally substituted with one or
more substituents, which may be independently selected from the
group consisting of --NO.sub.2, --CN, halogen (e.g., --F, --Cl,
--Br or --I), (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and
halo(C1-C3)alkoxy.
[0063] A substituted benzyl group may be optionally substituted at
one or more meta, ortho or para positions with one or more
substituents, which may be independently selected from the group
consisting of --NO.sub.2, --CN, halogen (e.g., --F, --Cl, --Br or
--I), (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and
halo(C1-C3)alkoxy.
[0064] Values and particular values for the variables depicted in
reaction 1 are provided in the following paragraphs:
[0065] P.sub.1 is an alcohol protecting group. In one embodiment,
P.sub.1 is THP or TBDMS. Alternatively, P.sub.1 is THP.
[0066] R is --(CH.sub.2).sub.nX or P.sub.1. In one embodiment, R is
selected from the group consisting of methyl, benzyl,
--CH.sub.2COOMe, --CH.sub.2COOCH.sub.2Ph, THP and TBDMS.
Alternatively, R is methyl.
[0067] X is --H, phenyl, --CN, --OR.sub.1 or COOR.sub.1. In one
embodiment, X is --H. In another embodiment, X is an optionally
substituted phenyl. Alternatively, X is unsubstituted phenyl. In
one embodiment, when n is 0, X is not --CN, --OR.sub.1 or
COOR.sub.1.
[0068] R.sub.1 is an alkyl, THP or TBDMS. In one embodiment,
R.sub.1 is a (C1-C3)alkyl. Alternatively, R.sub.1 is methyl. In
another alternative, R.sub.1 is benzyl.
[0069] n is 0, 1, 2 or 3. In one embodiment, n is 1. Alternatively,
n is 0.
[0070] R.sub.2 and R.sub.3 are each independently --H or an alkyl.
In one embodiment, R.sub.2 and R.sub.3 are both --H. In another
embodiment, R.sub.2 and R.sub.3 are each independently --H or a
(C1-C3)alkyl. Alternatively, R.sub.2 and R.sub.3 are both methyl.
In another alternative, R.sub.2 is --H and R.sub.3 is methyl.
[0071] Z is --H, cycloalkyl or phenoxy. In one embodiment, Z is
--H. Alternatively, Z is a (C3-C6)cycloalkyl. In another
alternative, Z is
##STR00015##
wherein R.sub.4 is --H, --Cl, --Br, --F, --I, halo(C1-C3)alkyl,
(C1-C3)alkyl, or --O--(C1-C3)alkyl. In one embodiment, R.sub.4 is
R.sub.4 is --H, --Cl, --Br, --F, --I, --CF.sub.3, -Me or --OMe.
[0072] p is 1, 2, 3, 4 or 5. In one embodiment, p is 5. In another
embodiment, p is 1.
[0073] P.sub.2 is an alcohol protecting group. In one embodiment,
P.sub.2 is THP or TBDMS. Alternatively, P.sub.2 is TBDMS.
[0074] In one embodiment, the alkyne of structural formula (a) is
selected from the following:
##STR00016##
[0075] wherein: q is 1, 2, 3 or 4; and R.sub.4 is as described
above.
[0076] In one embodiment, for reaction 1 described above, P.sub.1
may be THP.
[0077] In another embodiment, R may be selected from the group
consisting of methyl, benzyl, --CH.sub.2COOMe,
--CH.sub.2COOCH.sub.2Ph, THP and TBDMS. Alternatively, R is
methyl.
[0078] In yet another embodiment, R is methyl and P.sub.1 is
THP.
[0079] In yet another embodiments, R is --CH.sub.2CO.sub.2R.sub.1,
wherein R.sub.1 is an alkyl group, such as a straight or branched
C1-C5 alkyl group, or a substituted or unsubstituted benzyl group,
and P.sub.1 is tetrahydrofuranyl (THP), benzyl, 2,4-dinitrobenzyl,
methoxymethyl (MOM), tertiarybutyldimethylsilyl (TBDMS),
tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
[0080] When reaction 1 is carried out in the presence of a chiral
inducing agent, the reaction may yield a product having
predominantly S configuration of the hydroxyl group at the benzylic
carbon position. A "chiral inducing agent" is a compound that is
used to create stereoselectivity at a chiral center. For example,
(+)-N-methylephiderine may be used as the chiral inducing agent for
reaction 1 described above. In one embodiment, at least 70%, 80%,
90%, 95%, 97%, 98%, 99%, 99.5%, 99.9% or 100% by weight of the
product of reaction 1 is represented by structural formula (A),
i.e., the compound prepared by reaction 1 has at least 40%, 60%,
80%, 90%, 94%, 96%, 98%, 99.0%, 99.8% or 100% chiral purity.
[0081] The compound of structural formula (A) can be subsequently
converted to a prostacyclin derivative such as treprostinil
according to Scheme 2, reaction steps 2-9.
##STR00017## ##STR00018##
In Scheme 2', values and particular values for R, R.sub.2, R.sub.3,
p, Z and P.sub.1 are as described above for structural formula
(A'); P.sub.2 is an alcohol protecting group (e.g., TBDMS); and m
is 1, 2, or 3.
[0082] In some embodiments, reaction 1 may be carried out in the
presence of a base and a zinc reagent. An exemplary zinc reagent
includes zinc triflate (Zn(OTf).sub.2). Suitable bases that may be
used include, for example, an alkali carbonate, an alkali
hydroxide, an amine and an ammonium hydroxide. In some embodiments,
Et.sub.3N may be preferred as the base.
[0083] In some embodiments, reaction 1 as described in any one of
the foregoing embodiments may be carried out in an organic solvent.
Suitable organic solvents include, for example, ethereal solvents
(e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran,
1,4-dioxane and dimethoxyethane), aromatic solvents (e.g., benzene
and toluene), chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol,
2-propanol), dimethylformamide, dimethyl sulfoxide and
acetonitrile. In one specific embodiment, reaction 1 may be carried
out in toluene.
[0084] U.S. Pat. Nos. 6,700,025, 6,809,223, 6,528,668 and 6,441,245
describe a method, which may be used for preparing some of the
compounds of structural formula (A). This method, depicted in
Scheme 1, however, includes 3 reaction steps.
##STR00019##
[0085] Compared to the prior art method, reaction 1 of the present
invention may have one or more of the following advantages: (1)
reaction 1 has high diastereoselectivity, wherein the product with
greater than 95% chiral purity can be obtained. (2) the prior
method requires 3-step synthesis; whereas the method (reaction 1)
of the present invention only has a single step, which shortens the
number of chemical steps needed; eliminates the tedious column
chromatographic purifications involved in the extra two steps and
saves manpower and large volume of solvents. (3) reaction 1 may be
carried out at room temperature, and therefore no cryogenic
reactors are needed; (4) reaction 1 is less expensive than the
prior art method as the prior art method involves the use of
expensive reagents as needed in the Corey asymmetric reduction. (5)
reaction 1 is an eco-friendly method as it does not require the use
of obnoxious borane-dimethyl sufide complex in the Corey asymmetric
reduction.
[0086] In some embodiments, the compound of structural formula (A)
may be subsequently converted to a prostacyclin derivative such as
treprostinil according to Scheme 2, reaction steps 2-9.
##STR00020## ##STR00021##
In Scheme 2, R and P.sub.1 are as described above for structural
formula (A); P.sub.2 is an alcohol protecting group; and m is 1, 2,
or 3.
[0087] The present application may be also directed to a method of
preparing a prostacyclin derivative represented by structural
formula (IX) or a pharmaceutically acceptable salt thereof
comprising reaction 1. In some embodiments, the method may also
optionally include one or more steps selected from the group
consisting of reaction 2, reaction 3, reaction 4, reaction 5,
reaction 6, reaction 7, reaction 8 and reaction 9 shown in Scheme 2
in conjunction with reaction 1 to make the prostaglandin derivative
(IX). For example, the method comprises the steps of reaction 1 and
reaction 3. Alternatively, the method may comprise the steps of
reaction 1, reaction 3, reaction 4, reaction 5 and reaction 6. In
another alternative, the method may comprise the steps of reaction
1, reaction 8 and reaction 9. In yet another alternative, the
method for preparing treprostinil comprises the steps of reaction
1, reaction 2, reaction 3, reaction 4, reaction 5, reaction 6,
reaction 7, reaction 8 and reaction 9.
[0088] As used herein, a "pharmaceutically acceptable salt" refers
to a salt that is useful in preparing a pharmaceutical composition
and is generally safe, non-toxic and neither biologically nor
otherwise undesirable pharmaceutical use.
[0089] Compounds with basic groups, such as amine groups, can form
pharmaceutically acceptable salts with pharmaceutically acceptable
acid(s). Suitable pharmaceutically acceptable acid addition salts
of the compounds of the invention include salts of inorganic acids
(such as hydrochloric acid, hydrobromic, phosphoric,
metaphosphoric, nitric, and sulfuric acids) and of organic acids
(such as, acetic acid, benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,
lactobionic, maleic, malic, methanesulfonic, succinic,
p-toluenesulfonic, and tartaric acids). Compounds with acidic
groups such as carboxylic acids can form pharmaceutically
acceptable salts with pharmaceutically acceptable base(s). Suitable
pharmaceutically acceptable basic salts include ammonium salts,
alkali metal salts (such as sodium and potassium salts) and
alkaline earth metal salts (such as magnesium and calcium salts).
Compounds with a quaternary ammonium group also contain a
counteranion such as chloride, bromide, iodide, acetate,
perchlorate and the like. Other examples of such salts include
hydrochlorides, hydrobromides, sulfates, methanesulfonates,
nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g.
(+)-tartrates, (-)-tartrates or mixtures thereof including racemic
mixtures], succinates, benzoates and salts with amino acids such as
glutamic acid. A particularly preferred salt is the diethanolamine
salt of treprostinil.
[0090] In one embodiment, the prostacyclin derivative (e.g.,
treprostinil) prepared according to the methods described herein
may have at least 40%, 60%, 80%, 90%, 94%, 96%, 98%, 99.0%, 99.8%
or 100% chiral purity.
[0091] In one embodiment, the prostacyclin derivative is
treprostinil represented by structural formula (IX-1) (i.e., m=1
for structural formula (IX).
[0092] In one embodiment, for structural formulas (I)-(VI) and (A),
R may be selected from the group consisting of methyl, benzyl,
--CH.sub.2COOMe, --CH.sub.2COOCH.sub.2Ph, THP and TBDMS. More
specifically, R is methyl.
[0093] In another embodiment, for structural formulas (I)-(V), (A)
and (a), P.sub.1 is THP.
[0094] In yet another embodiment, for structural formulas (II) and
(III), P.sub.2 is TBDMS.
[0095] In another embodiment, for reactions depicted in Scheme 2, R
is methyl, P.sub.1 is THP, P.sub.2 is TBDMS and m is 1.
[0096] In one embodiment, for methods of preparing a prostacyclin
derivative described herein, specific conditions and reagents for
reaction 1 are as described above.
[0097] For reaction 2 depicted in Scheme 2 above, compound (A) is
reacted with an alcohol protecting reagent to form the compound of
structural formula (II). An "alcohol protecting reagent" is a
reagent that converts a --OH group to --OP.sub.2. In one
embodiment, the alcohol protecting reagent is TBDMSCl.
[0098] In one embodiment, reaction 2 is carried out in the presence
of a base. Suitable base can be used includes, but is not limited
to, an alkali carbonate, an alkali hydroxide, an amine and an
ammonium hydroxide. More specifically, the base is an amine. Even
more specifically, the base is a mixture of imidazole and
dimethylaminopyridine (DMAP).
[0099] Reaction 2 can be carried out in a suitable solvent or a
solvent mixture. In one embodiment, reaction 2 is carried out in an
organic solvent, such as ethereal solvents (e.g., diethyl ether,
methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane and
dimethoxyethane), aromatic solvents (e.g., benzene and toluene),
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol,
2-propanol), dimethylformamide, dimethyl sulfoxide and
acetonitrile. In one embodiment, the solvent is methylene chloride
(CH.sub.2Cl.sub.2).
[0100] For reaction 3 depicted in Scheme 2, the compound of
structural formula (II) is converted to the compound of structural
formula (III) through a cobalt-mediated cyclization reaction. More
specifically, the cyclization reaction is carried out in the
presence of Co.sub.2(CO).sub.8.
[0101] In one embodiment, reaction 3 is carried out in an organic
solvent or a mixture of organic solvents. Suitable organic solvents
include, but are not limited to, ethereal solvents (e.g., diethyl
ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane and
dimethoxyethane), aromatic solvents (e.g., benzene and toluene),
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol,
2-propanol), dimethylformamide, dimethyl sulfoxide and
acetonitrile. More specifically, reaction 3 is carried out
initially in CH.sub.2Cl.sub.2 followed by removal of the solvent by
distillation. The reaction is subsequently carried out in
acetonitrile.
[0102] For reaction 4 depicted in Scheme 2, the compound of
structural formula (III) is hydrogenated with H.sub.2 to form the
compound of structural formula (IV). In one embodiment, the
hydrogenation reaction is carried out in the presence of a
hydrogenation catalyst. More specifically, the hydrogenation
reaction is carried out in the presence of Pd/C. In another
embodiment, the hydrogenation reaction is carried out in the
presence of a base, such as a alkali carbonate (e.g.,
K.sub.2CO.sub.3).
[0103] Reaction 4 can be carried out in an organic solvent, such as
ethereal solvents (e.g., diethyl ether, methyl tert-butyl ether,
tetrahydrofuran, 1,4-dioxane and dimethoxyethane), aromatic
solvents (e.g., benzene and toluene), chlorinated solvents (e.g.,
methylene chloride and 1,2-dichloroethane), alcohol solvents (e.g.,
methanol, ethanol, 2-propanol), dimethylformamide, dimethyl
sulfoxide and acetonitrile. More specifically, the reaction is
carried out in EtOH.
[0104] For reaction 5, the compound of structural formula (IV) is
reacted with a reducing agent to form the compound of structural
formula (V). A "reducing agent" is a reagent that can convert a
carbonyl functional group to an alcohol functional group. Suitable
reducing agents can be used include, but are not limited to,
NaBH.sub.4 and LiAlH.sub.4. More specifically, the reducing agent
is NaBH.sub.4. In one embodiment, reaction 5 is carried out in the
presence of a base, such as an alkali hydroxide (e.g. NaOH).
Reaction 5 can be carried out in an organic solvent, such as those
described above. More specifically, the reaction is carried out in
EtOH.
[0105] For reaction 6, the compound of structural formula (V) is
reacted with a strong acid, such as p-toluenesulfonic acid (pTsOH),
TFA, TfOH, or hydrochloric acid, to form the compound of structural
formula (VI). More specifically, the acid is pTsOH. Reaction 6 can
be carried out in an organic solvent, such as those described
above. More specifically, the solvent is MeOH.
[0106] For reaction 7, the compound of structural formula (VI) is
reacted with Ph.sub.2PH in the presence of a base. In one
embodiment, the base is alkyllithium. More specifically, the base
is nBuLi. Reaction 7 can be carried out in an organic solvent.
Exemplary organic solvents are described above. In one embodiment,
reaction 7 is carried out in tetrahydrofuran (THF).
[0107] For reaction 8, the compound of structural formula (VII) is
reacted with X.sub.1(CH.sub.2).sub.mCN to form the compound of
structural formula (VIII), wherein X.sub.1 is a leaving group and m
is 1, 2 or 3. A "leaving group" is a moiety that can easily be
displaced by a nucleophile. For example, a leaving group is a
halide (e.g., --Cl, --Br, --I), a sulfonate group (e.g.,
MeSO.sub.2O--, CF.sub.3SO.sub.2O--,
CH.sub.3C.sub.6H.sub.4SO.sub.2O--, or C.sub.6H.sub.5SO.sub.2O--).
More specifically, X.sub.1 is --Cl and m is 1.
[0108] In one embodiment, reaction 8 is carried out in the presence
of a base, such as an alkali carbonate (e.g., K.sub.2CO.sub.3).
[0109] Reaction 8 can be carried out in an organic solvent, such as
those described above. More specifically, the solvent is
acetone.
[0110] For reaction 9, the compound of structural formula (VIII) is
reacted with a base, such as an alkali hydroxide (e.g., NaOH). The
reaction can be carried out in an organic solvent, such as those
described above. In one embodiment, the reaction is carried out
EtOH.
[0111] Also included in the present invention is the prostacyclin
derivatives represented by structural formula (IX) (e.g.,
treprostinil) prepared by methods described herein.
[0112] In some embodiments, a prostacyclin derivative represented
by structural formula (IX), such as treprostinil, or a
pharmaceutically acceptable salt thereof may be prepared using one
or more reactions from Scheme 3:
##STR00022##
[0113] In Scheme 3, R.sub.1 may be an alkyl group or a substituted
or unsubstituted benzyl group, and P.sub.1 are as described above
for structural formula (A); P.sub.2 is an alcohol protecting group;
and m is 1, 2, or 3.
[0114] Compound (7) in Scheme 3 corresponds to the prostacyclin
derivative represented by structural formula (IX) earlier in the
disclosure, compound (2) in Scheme 3 corresponds to the compound of
structural formula (A) earlier in the disclosure, while Step 2 in
corresponds to reaction 1 earlier in the disclosure.
[0115] In some embodiments, a method of preparing a prostacyclin
derivative represented by structural formula (IX) or a
pharmaceutically acceptable salt thereof may comprising Step 2 of
Scheme 3. The method may also optionally include one or more steps
selected from the group consisting of Step 1, Step 3, Step 4, Step
5 and Step 6 shown in Scheme 3 in conjunction with Step 2 to make
the prostaglandin derivative (IX). For example, the method
comprises Step 2 and Step 3. Alternatively, the method may comprise
Step 2, Step 3 and Step 4. In another alternative, the method may
comprise the steps of Step 2, Step 5 and Step 6. In another
alternative, the method may comprise Step 1 and Step 2. In yet
another alternative, the method for preparing treprostinil may
comprise Step 1, Step 2, Step 3, Step 4, Step 5 and Step 6.
[0116] The reactions of scheme 3 may be particularly useful for R
is --(CH.sub.2).sub.mCO.sub.2R.sub.1, wherein m=1, 2 or 3 and
R.sub.1 is an alkyl group, such as a straight or branched C1-C5
alkyl group, or a substituted or unsubstituted benzyl group.
Compared to prior art methods, such as those disclosed in U.S. Pat.
Nos. 6,700,025, 6,809,223, 6,528,668 and 6,441,245, the method of
Scheme 3 may include fewer steps for preparing a prostacyclin
derivative represented by structural formula (IX).
[0117] Step 1 of Scheme 3 may be performed by reacting compound 1
with R.sub.2COOR.sub.1, wherein R.sub.2 may be a leaving group such
as halogen, e.g. Cl, I, or Br, tosylate, mesylate or triflate, and
R.sub.1 is an alkyl group or a substituted or unsubstituted benzyl
group. In some embodiments, the reaction may be carried out in the
presence of a base, which may be an alkali carbonate, such as
K.sub.2CO.sub.3. In some embodiments, the base may be potassium
tertiary butoxide (t-BuOK), sodium hydride (NaH), sodium hydroxide
(NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH) etc.
The reaction may be carried out in a number of solvents including
butanone, propanone, N,N-dimethyl formamide (DMF), dimethoxyethane
(DME), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene and
acetone.
[0118] Step 2 of Scheme 3 may be performed as described above for
reaction 1 of scheme 2.
[0119] Step 3 of Scheme 3 may be performed by compound (A) with an
alcohol protecting reagent to form the compound of structural
formula (4). An "alcohol protecting reagent" is a reagent that
converts a --OH group to --OP.sub.2. In some embodiments, P.sub.2
may be tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl
(TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group). The
respective alcohol protective reagents may be TBDMSCl or TBDMSOTf
for TBDMS, TESCl for TES, TBDPSCl for TBDPS and tritylchloride for
trityl. In some embodiments, TBDMS may be preferred as P.sub.2 and
TBDMSCl may be preferred as the alcohol protecting reagent.
Chemical formula of exemplary protective reagents is presented
below.
##STR00023##
[0120] In one embodiment, Step 3 of Scheme 3 may be carried out in
the presence of a base. Suitable base that may be used includes,
but is not limited to, an alkali carbonate, an alkali hydroxide, an
amine and an ammonium hydroxide. In one specific embodiment, the
base may an amine, such as of imidazole, 4-dimethylaminopyridine
(DMAP) or a mixture thereof.
[0121] Step 3 of Scheme 3 may be carried out in a suitable solvent
or a solvent mixture. In one embodiment, Step 3 of Scheme 3 may be
carried out in an organic solvent, such as ethereal solvents (e.g.,
diethyl ether, methyl tert-butyl ether, tetrahydrofuran,
1,4-dioxane and dimethoxyethane), aromatic solvents (e.g., benzene
and toluene), chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane), dimethylformamide, dimethyl sulfoxide and
acetonitrile. In one embodiment, the solvent may be methylene
chloride (CH.sub.2Cl.sub.2).
[0122] Step 4 of Scheme 3 may be performed by converting the
compound of structural formula (4) to the compound of structural
formula (5). In some embodiments, such conversion may be performed
by a cobalt-mediated cyclization reaction. Such cyclization
reaction may be carried out, for example, in the presence of
Co.sub.2(CO).sub.8.
[0123] In one embodiment, Step 4 of Scheme 3 may be carried out in
an organic solvent or a mixture of organic solvents. Suitable
organic solvents include, but are not limited to, ethereal solvents
(e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran,
1,4-dioxane and dimethoxyethane), aromatic solvents (e.g., benzene
and toluene), chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane), alcohol solvents (e.g., methanol, ethanol,
2-propanol), dimethylformamide, dimethyl sulfoxide and
acetonitrile. In some embodiments Step 4 of Scheme 3 may be carried
out in 1,2-dimethoxyethane. followed by removal of the solvent by
distillation.
[0124] In some embodiments, Step 4 may be carried out using from
about 2 to 15 mol % or from 3 to 12 mol % or from 5 to 10 mol % or
any subrange within the above stated ranges of Co.sub.2(CO).sub.8.
In some embodiments, Step 4 may be carried out under atmosphere of
carbon monoxide using from about 2 to 15 mol % or from 3 to 12 mol
% or from 5 to 10 mol % or any subrange within the above stated
ranges of Co.sub.2(CO).sub.8. Such conditions may save cost and/or
avoid laborious column chromatography and hence save time compared
to stoichiometric Pauson-Khand cyclization such as the one used,
for example, in U.S. Pat. No. 6,765,117.
[0125] In some embodiments, the reaction of Step 4 may be carried
out under atmospheric pressure. Yet in some embodiments, the
reaction of step of Step 4 may be carried at a pressure that is
higher than the atmospheric pressure. The use of the elevated
pressure may make the reaction of Step 4 go faster compared the
reaction under the atmospheric pressure. In some embodiments, the
reaction of Step 4 may be carried out at a pressure ranging from 10
psi to 250 psi or from 20 psi to 250 psi or from 20 psi to 200 psi
or any subrange within these ranges.
[0126] Step 5 of Scheme 3 may be performed by hydrogenating the
compound of structural formula (5) to form a hydrogenated compound
of formula (6) or (6'). The hydrogenation reaction may involve
reacting the compound of structural formula (5) with H.sub.2. In
some embodiments, the hydrogenation reaction may be carried out in
the presence of a hydrogenation catalyst. Such hydrogenation
catalyst may comprise a metal hydrogenation catalyst, such as Pd.
In some embodiments, the hydrogenation catalyst may be Pd/C. In
some embodiments, the hydrogenation reaction may be carried out in
the presence of a base, which may be a alkali carbonate, such as
K.sub.2CO.sub.3.
[0127] Step 5 of Scheme 3 may be carried out in an organic solvent,
such as ethereal solvents (e.g., diethyl ether, methyl tert-butyl
ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane), aromatic
solvents (e.g., benzene and toluene), chlorinated solvents (e.g.,
methylene chloride and 1,2-dichloroethane), alcohol solvents (e.g.,
methanol, ethanol, 2-propanol), dimethylformamide, dimethyl
sulfoxide and acetonitrile.
[0128] When R.sub.1 is an alkyl group Step 5 may result in the
hydrogenated compound of structural formula (6):
##STR00024##
[0129] When R.sub.1 is a substituted of unsubstituted benzyl group
Step 5 may result in the hydrogenated compound of structural
formula (6'):
##STR00025##
which has its benzyl group cleaved as the result of
hydrogenation.
[0130] Step 6 of Scheme 3 may be performed by converting the
hydrogenated compound represented by structural formula (6) or (6')
to a compound represented by structural formula (7) or (IX). In
some embodiments, the conversion of Step 6 may be performed in the
presence of a reducing agent, which may be used for the reduction
of the ketone to alcohol on the cyclopentyl ring. The reducing
agent may be, for example, NaBH.sub.4, NaCNBH.sub.3 or LiBH.sub.4.
In some embodiments, the reducing agent may be used together with a
base, which may be used for hydrolysis of the ester group to acid.
The base may be, for example, NaOH, KOH, LiOH or Ba(OH).sub.2. In
some embodiments, step 6 may be carried in the presence of an acid,
which may be used to obtain a free acid from the ester group after
its hydrolysis and/or to remove the protection group P.sub.1 from
the side chain. In some embodiments, the acid may be, for example,
HCl, acetic acid, formic acid, trifluoroacetic acid, para-toluene
sulfonic acid, dilute H.sub.2SO.sub.4, dilute HNO.sub.3 or a
polymer bound acidic resin, such as Amberlyst-15 or Dowex 50WX-X8.
Solvents, which may be used for Step 6's conversion, may include
water and/or organic solvents, such as alcohols, for example
ethanol. In some embodiments, Step 6 may be performed in the
presence of two or more of the reducing agent, the base and the
acid. In some embodiments, Step 6 may be carried out in the
presence of all three of the reducing agent, the base and the
acid.
[0131] Step 6 may allow performing one or more of the following in
a single pot: reduction of the ketone of compound (6) to alcohol of
compound (7), hydrolysis of the ester group of compound (6) to a
free acid of compound (7) and removal of the P.sub.1 protective
group of compound (6).
[0132] For example, conversion of compound of structural formula
(6), when R.sub.1 is an alkyl group, the conversion reaction may
accomplish cleaving of the protective group P.sub.1 and ester
hydrolysis of R to a free acid in a single pot. This conversion may
also include reduction of the ketone of compound (6) to alcohol of
compound (7).
[0133] The present invention also relates to intermediates for
synthesis a prostacyclin derivative represented by structural
formula (IX), such as compounds of formulas (2), (3), (4), (5) and
(6, 6') in Scheme 3.
[0134] The invention is further illustrated by, though in no way
limited to, the following examples.
Example 1
Preparation of Chiral Benzyl Alcohol (A-1)
##STR00026##
[0136] A 50-mL, two-necked, round-bottom flask equipped with a
mechanical stirrer was charged with zinc triflate (2.16 g, 0.0059
mol) and (+)-N-methylephiderine (0.814 g, 0.0045 mol) in toluene
(10 mL). To this mixture triethyl amine was added (0.459 g, 0.0045
mol) and this gelatinous mixture was stirred at ambient temperature
for 30-60 minutes. To this mixture was then treated with a solution
of alkyne (1.08 g, 0.0045 mol) in toluene (1 mL), stirred at
ambient temperature for 15 minutes followed by solution of aldehyde
(0.250 g, 0.0014 mol). Progress of the reaction was monitored by
TLC (completion of the reaction was monitored by thin layer
chromatography (TLC) using a thin layer silica gel plate; eluent:
20% ethyl acetate in hexanes). After stirring the mixture for 3 h
TLC indicated completion of reaction. At this stage reaction
mixture was quenched by slow addition of saturated ammonium
chloride (10 mL). This was stirred for 5-10 minutes and organic
layer containing desired compound was separated. Aqueous layer was
washed with ethyl acetate (10 mL). The combined organic layers were
washed with brine (15 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo to obtain a crude product (2.0
g). The crude product was purified by column chromatography using
250-400 mesh silica gel. A solvent gradient of ethyl acetate in
hexanes (5-20%) was used to elute the product from the column. All
fractions containing the desired product were combined and
concentrated in vacuo to give pure chiral benzyl alcohol A-1 (0.360
g, .about.87%) compound was characterized by .sup.1H, .sup.13C NMR,
IR, LCMS and chiral HPLC data. .sup.1H NMR (CDCl.sub.3, 300 MHz):
.delta. 0.87 (t, 3H), 1.18-1.86 (m, 17H), 2.28 (dt, 1H), 2.34-2.45
(m, 2H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.63-3.75 (m, 1H),
3.81 (s, 3H, OCH3), 3.83-3.92 (m, 1H), 4.62-4.66 (m, 1H), 4.89-5.05
(m, 2H), 5.59-5.61 (merged two s, 1H), 5.91-6.04 (m, 1H), 6.85-6.82
(d, 1H), 7.20-7.26 (m, 1H), and 7.31-7.36 (m, 1H); .sup.13C NMR
(CDCl.sub.3, 75 MHz): .delta. 14.13, 14.18, 14.98, 15.56, 19.96,
21.14, 22.71, 24.77, 25.34, 25.57, 29.51, 31.17, 31.23, 32.07,
32.19, 32.69, 33.51, 33.94, 35.13, 55.86, 60.49, 62.12, 62.18,
62.82, 75.36, 75.89, 80.20, 80.53, 86.97, 87.42, 97.31, 98.06,
110.63, 114.80, 119.18, 119.27, 125.86, 127.44, 127.50, 137.15,
140.78, 157.68; IR: 3411, 2230, 1638, 1259, 1133, 1023, 755
cm.sup.-1; MS (m/z): [M+Na].sup.+437.35.
Example 2
Preparation of Treprostinil (IX-1)
[0137] Treprostinil can be prepared according to Scheme 4.
Exemplary reaction conditions for making the chiral benzyl alcohol
(compound A-1) are described in Example 1. Exemplary conditions for
other reactions depicted in Scheme 3 are as described in U.S. Pat.
Nos. 6,700,025, 6,809,223, 6,528,668 and 6,441,245. The entire
teaching of all these documents are incorporated herein by
reference.
##STR00027## ##STR00028##
Example 3
Preparation of Treprostinil
##STR00029##
[0139] The inventors have developed a stereoselective route for the
synthesis of treprostinil (7) starting from aldehyde (1) and side
chain (SCiv). This route may involve direct stereoselective
addition of an alkyne to starting
2-Allyl-3-[(carbomethoxy)methoxy]benzaldehyde (2) and illustrates
the synthetic utility of catalytic a Pauson-Khand Cyclization (PKC)
for the synthesis of a drug substance, treprostinil (7, UT-15).
O-alkylation of the readily available 3-hydroxy-2-allylbenzaldehyde
(Step 1-->2) with methylbromoacetate provided the required
starting material (2) to accomplish this synthesis. The steps in
the synthesis may involve a stereoselective addition of an alkyne,
and an efficient stereoselection effected in the PKC of a
benzoenyne under the agency of a protective group P.sub.1, such as
benzylic OTBDMS group. This protective group can serve as a
temporary stereodirecting group and may be conveniently removed via
hydrogenolysis concomitantly in the catalytic hydrogenation of the
enone PKC product. At the final step, reduction, P.sub.1 cleavage
and ester hydrolysis may be accomplished in one pot to obtain
desired prostaglandin analog product, such as treprostinil (7).
[0140] The advantage of the present chemistry may include, but not
limited to: 1) direct stereoselective addition of alkyne to
aldehyde; 2) this route may also eliminate the need of four steps
in the prior art synthesis of prostacyclin derivatives disclosed,
for example, in Moriarty et al (U.S. Pat. No. 6,765,117). In
particular, the present route may eliminate one or more of the
following steps of the prior art synthesis (U.S. Pat. No.
6,765,117):
1) Grignard addition step (compound 5-compound 6 in U.S. Pat. No.
6,765,117); 2) PCC oxidation step (compound 6-compound 7 in U.S.
Pat. No. 6,765,117); 3) Chiral reduction step, aka as Corey
reduction (compound 7-compound 8 in U.S. Pat. No. 6,765,117); 4)
demethylation of phenyl methyl ester (compound 13-compound 14 in
U.S. Pat. No. 6,765,117).
[0141] The present synthesis scheme may not only shorten the number
of chemical steps to obtain treprostinil but also eliminate the
tedious column chromatographic purifications required in the prior
art methods, such as the one in U.S. Pat. No. 6,765,117 at
intermediate steps. Such elimination of the prior art
chromatographic purifications may significantly save manpower and
large volumes of solvents. For example, the prior art route of U.S.
Pat. No. 6,765,117 has 15 steps and requires chromatographic
purifications on all them but one (compound 11-compound 12). The
present synthesis has only 6 steps and may include chromatographic
purification in at most three steps (steps 2, step 3 and step
4).
[0142] The present synthesis scheme may enable performing the
reactions at room temperature without the need for cryogenic
reactors, which are required in the prior art methods, such as the
one in U.S. Pat. No. 6,765,117. For example, the prior art route of
U.S. Pat. No. 6,765,117 requires cryogenic reactors in chiral
reduction step (compound 7-compound 8) and in demethylation of
phenyl methyl ester (compound 13-compound 14).
[0143] The present synthesis does not involve use of expensive
reagents which are required in the prior art methods, such as the
one in U.S. Pat. No. 6,765,117. For example, the prior art route of
U.S. Pat. No. 6,765,117 in the chiral reduction step (compound
7-compound 8) used starting compound (B) for Corey reagent (B+C),
which is an expensive reagent. Corey reagent (B+C) itself is also
an expensive reagent.
[0144] This report provides the experimental details on the
synthesis of treprostinil (7) below.
Step 1: 2-Allyl-3-[(carbomethoxy)methoxy]benzaldehyde (2)
##STR00030##
TABLE-US-00001 [0145] TABLE 1 Name MW Amount mol Aldehyde (1)
162.18 2.5 g 0.015 methylbromoacetate 152.97 2.5 g 0.016
K.sub.2CO.sub.3 138.21 6.3 g 0.045 Acetone NA 50 ml NA
[0146] Procedure: A 100-mL round-bottom flask equipped with a
magnetic stirrer and stir bar was charged with a solution of
3-hydroxy-2-allylbenzaldehyde (1) (2.5 g in 50 mL acetone),
methylbromoacetate (2.5 g, 1.10 eq.) and powdered potassium
carbonate (6.3 g, 3.0 eq.). The mixture was stirred at 40.degree.
C. for four hours and progress of reaction was monitored by TLC
(Note 1). After completion of the reaction, the suspension was
filtered and the filtrate was evaporated in vacuo to afford a crude
semi-solid mass. This was slurried in 30 mL of hexanes and stirred
for 15 minutes. A solid crashed out of the hexanes and was
collected by filtration to obtain compound (2) as an off-white
solid; yield 3.48 g (99%), mp 46-47.degree. C. The structure was
consistent with spectral data. IR (neat) cm.sup.-1: 3084, 2761,
1735, 1692; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.78 (s, 3H),
3.91 (d, 2H, J=6 Hz), 4.71 (s, 2H), 4.98 (m, 2H), 6.03 (m, 1H),
6.96 (d, 1H, J=8 Hz), 7.33 (dd, 1H, J=8 Hz), 7.52 (d, 1H, J=8 Hz);
.sup.13C NMR (CDCl.sub.3, 75 MHz) 8 28.32, 52.37, 66.01, 115.75,
117.05, 123.73, 127.55, 131.73, 135.40, 136.58, 156.23, 169.09,
192.08; MS: (M+1) 235.41.
[0147] Note 1: Completion of the reaction was monitored by TLC
using a thin layer silica gel plate; eluent: 20% ethyl acetate in
hexanes.
Step 2: Preparation of chiral benzyl alkynol (3)
##STR00031##
TABLE-US-00002 [0148] TABLE 2 Name MW Amount mol Aldehyde (2)
234.25 0.50 g 0.0026 Alkyne side chain 238.37 1.57 g 0.0065 (Sciv)
Zinc triflate 363.51 3.17 g 0.0087 (+)-N-Methylephedrine 179.26
1.22 g 0.0068 Triethylamine 101.19 0.68 g 0.0068 Toluene NA 10 ml
NA
[0149] Procedure: A 50-mL, two-necked, round-bottomed flask
equipped with a magnetic stirrer and stir bar was charged with zinc
triflate (3.17 g, 0.0087 mol) and (+)-N-methylephedrine (1.22 g,
0.0068 mol) in toluene (5 mL). To this mixture triethylamine was
added (0.68 g, 0.0068 mol) and this gelatinous mixture was stirred
at ambient temperature for 1-2 h. To this mixture was then added a
solution of alkyne (1.57 g, 0.0065 mol) in toluene (4 mL), stirred
at ambient temperature for 15-30 minutes followed by addition of a
solution of aldehyde (2) (0.50 g, 0.0026 mol in 1-2 mL toluene).
Progress of the reaction was monitored by TLC (Note 1). After
stirring the mixture at room temperature for 16 h, TLC indicated
completion of reaction. The reaction mixture was quenched by slow
addition of water (10 mL). This was stirred for 5-10 minutes and
organic layer containing desired compound was separated. The
aqueous layer was extracted with ethyl acetate (10 mL). The
combined organic layers were washed with brine (10 mL), dried over
anhydrous sodium sulfate, filtered and the filtrate concentrated in
vacuo to obtain a crude product. The crude product wa.about.
purified by column chromatography using 250-400 mesh silica gel. A
solvent gradient of ethyl acetate in hexanes (5-20%) was used to
elute the product from the column. All fractions containing the
desired pure product were combined and concentrated in vacuo to
give pure chiral benzyl alkynol (3,700 mg, -70%). The structure was
consistent with spectral data.
[0150] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 0.84 (t, 3H, J=6
Hz), 1.25-1.82 (m, 17H), 2.28 (t, 1H, J=6 Hz), 2.34-2-42 (m, 2H),
3.42-3.52 (m, 1H), 3.61-3.74 (m, 3H), 3.78 (s, 3H), 3.81-3.95 (m,
1H), 4.61 (s, 2H), 4.68 (m, 1H), 4.94-5.01 (m, 2H), 5.62 (br s,
1H), 5.97-6.07 (m, 1H), 6.76 (d, 1H, J=8 Hz), 7.16-7.27 (m, 1H),
7.38-7.43 (m, 1H); .sup.13C NMR (CDCl.sub.3, 75 MHz) 84.75, -4.38,
-3.49, 14.12, 14.16, 14.84, 15.52, 18.06, 18.38, 20.04, 20.24,
22.70, 24.76, 25.25, 25.56, 25.72, 25.94, 29.67, 31.22, 31.28,
32.05, 32.11, 32.65, 33.41, 34.01, 35.08, 52.22, 62.36, 62.84,
63.09, 66.04, 75.41, 76.44, 76.68, 80.83, 81.22, 85.57, 86.01,
97.31, 98.85, 110.89, 114.80, 119.77, 119.82, 125.56, 127.11,
127.16, 136.46, 136.52, 142.66, 142.73, 155.83, 169.68; MS: (M+Na)
495.6.
[0151] Note 1: Completion of the reaction was monitored by thin
layer chromatography (TLC) using a thin layer silica gel plate;
eluent: 20% ethyl acetate in hexanes.
Step 3: Preparation of Chiral Benzylalkynyl
tert.-butyldimethylsilyl ether (4)
##STR00032##
TABLE-US-00003 [0152] TABLE 3 Name MW Amount Mol Chiral
benzylalkynol 472.62 0.680 g 0.0014 t-butyldimethylsilyl chloride
150.73 0.282 g 0.0018 Imidazole 68.0 0.127 g 0.0018
4-(Dimethylamino)pyridine 122.17 0.167 g 10 mol % Dichloromethane
NA 30.0 mL NA
[0153] Procedure: A 50-mL, two-necked, round-bottomed flask
equipped with a magnetic stirrer and stir bar was charged with a
solution of chiral benzylalkynol (3) (0.680 g, 0.0014 mol) in
dichloromethane (30 mL) under argon. To this solution, imidazole
(0.127 g, 0.0018 mol) and 4-(dimethylamino)pyridine (0.176 g, 10
mol %) were added while stirring at room temperature. The stirring
was continued until a clear solution was obtained. To this solution
t-butyldimethylsilyl chloride (0.282 g, 0.0018 mol) was added
slowly while stirring. The reaction mixture was stirred at room
temperature for approximately 3-4 h (Note 1). The reaction was
quenched by addition of a saturated ammonium chloride solution (10
mL). The organic layer was separated and washed with brine (10 mL),
dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by column chromatography using 250-400 mesh
silica gel and eluted with a gradient solvent of ethyl acetate in
hexanes (2-12%). The fractions containing the desired compound were
evaporated in vacuo to yield benzyl alkynyl t-butyldimethylsilyl
ether (4) as a colorless, viscous liquid (0.800 g, 94%). The
structure was consistent with spectral data.
[0154] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 0.07-0.13 (four
merged s, 6H), 0.83 (merged t, 3H), 0.89-0.91 (two merged s, 9H),
1.24-1.84 (m, 10H), 2.18-2.34 (m, 2H), 3.39-3.69 (m, 3H), 3.78 (s,
3H), 3.81-3.91 (m, 1H), 4.55-4.56 (m, 1H), 4.62 (s, 2H), 4.96-4.98
(m, 2H), 5.57 (br s, 1H), 5.92-6.01 (m, 1H), 6.66 (d, 1H, J=8 Hz),
7.17 (two dd, 1H, J=8 Hz), 7.30 (d, 1H, J=8 Hz).
[0155] Note 1: Completion of the reaction was monitored by TLC
using a thin layer silica gel plate; eluent: 20% ethyl acetate in
hexanes.
Step 4: Preparation of Tricyclicenone (5)
##STR00033##
TABLE-US-00004 [0156] TABLE 4 Name MW Amount Mole Benzyl alkynyl
t-butyldimethylsilyl 584.65 0.100 g 0.00017 ether (4)
Octacarbonyldicobalt 341.95 0.0030 5 mol % 1,2-Dimethoxyethane NA
10 ml NA
[0157] Procedure: A 50-mL round-bottomed flask equipped with a
magnetic stirrer and stir bar was charged with a solution of
benzylalkynyl tert.-butyldimethylsilyl ether (4) (0.10 g) in
1,2-DME (10 mL), and was degassed by bubbling argon through the
solution for 2-3 minutes. To this solution was added
CO.sub.2(CO).sub.8 (0.003 g) and the mixture was stirred at room
temperature under an atmosphere of carbon monoxide (CO, using
balloon). After 30 minutes the reaction mixture was heated to
60-65.degree. C. using an oil bath for 6 h (Note 1). After cooling
to room temperature, 1,2-DME (solvent) was evaporated in vacuo to
yield a crude, gummy compound that was purified by flash
chromatography on silica gel using 5-20% ethyl acetate in hexanes.
Fractions containing the desired compound were collected and
evaporated in vacuo to yield tricyclic enone (5) (102 mg, 83%). The
structure was consistent with spectral data. IR (neat) cm, 1: 2928,
1728, 1702; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 0.02-0.13 (m,
6H), 0.80 (merged s, 9H), 0.81-0.88 (m, 1H). 1.18-2.61 (m, 16H),
2.71 (dd, 1H, J=6 Hz), 3.32-3.60 (m, 4H), 3.79 (merged s, 3H),
3.80-3.92 (m, 1H), 4.56 (merged d, 1H), 4.60 (merged s, 2H), 5.47
and 5.53 (two s, 1H), 6.63, 1H, J=8 Hz), 6.97 (dd, 1H, J=8 Hz),
7.19 (dd, 1H, J=8 Hz); .sup.13C NMR (CDCl.sub.3, 75 MHz) 8-4.20,
4.08, 14.17, 18.15, 20.13, 22.69, 24.84, 25.71, 31.27, 32.14,
33.29, 33.93, 42.19, 52.34, 62.86, 65.50, 76.68, 97.24, 110.19,
123.28, 125.74, 127.31, 137.52, 137.95, 155.18, 169.44, 209.60.
[0158] Note 1: Completion of reaction was monitored by TLC using a
thin layer silica gel plate; eluant: 20% ethyl acetate in hexanes.
After 3 h, TLC showed presence of starting material. At this stage
extra 5 mol % cobalt catalyst was added at room temperature and
reaction was again heated at 60-65.degree. C. until completion
(total reaction time 6 h)
Step 5: Preparation of Tricyclic ketone (6)
##STR00034##
TABLE-US-00005 [0159] TABLE 5 Name MW Amount Mole Tricyclic enone
(5) 614.90 0.10 g NA Palladium on charcoal NA 0.01 g NA (50% wet)
Potassium carbonate NA 0.010 NA Methanol NA 10.0 ml NA Water NA
1.00 ml NA
[0160] Procedure: A 200-mL round-bottom flask equipped with a
magnetic stirrer and stir bar was charged with a solution of
tricyclic enone (5) (0.10 g) in methanol (10.0 mL) and aqueous
K.sub.2CO.sub.3 (0.010 g in 1.0 mL water). To this solution, Pd/C
(0.010 g, 50% wet) was added while stirring at room temperature.
The reaction vessel was evacuated and pressurized with hydrogen gas
using a balloon. The reaction mixture was hydrogenated at balloon
pressure overnight (.about.16 h) at ambient temperature. After 16
h, the reaction was monitored by TLC, infra-red (IR) and proton NMR
(Note 1). At this stage the reaction mixture was filtered through a
pad of Celite (.about.4 g). The Celite pad was washed with methanol
(.about.50 mL). The combined filtrates were evaporated in vacuo to
give crude tricyclic ketone (6) and the crude product was purified
by column chromatography using 250-400 mesh silica gel. A solvent
gradient of ethyl acetate in hexanes (5-35%) was used to elute the
product from column. The fractions containing desired product were
evaporated in vacuo to yield tricyclic ketone (6) (0.035 g, 44%).
IR (neat) cm.sup.-1 2929, 1736, 1679; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 0.87 (br t, 3H), 1.21-3.12 (m, 27H), 3.42-3.53 (m,
1H), 3.55-3.68 (m, 1H), 3.79 (s, 3H), 3.86-3.95 (m, 1H), 4.61-4.69
(m, 1H), 4.64 (merged s, 2H), 6.53-6.56 (m, 1H), 6.74-6.81 (m, 1H),
7.06-7.08 (m, 1H).
[0161] Note 1: Completion of the hydrogenation was checked by
monitoring the change in the IR carbonyl stretch frequency
[starting material (tricyclic enone) .about.1728 cm.sup.-1, product
(tricyclic ketone)-1736 cm.sup.-1 and proton NMR. The reaction
mixture was evacuated and then purged with argon. A small aliquot
of reaction mixture was sampled, filtered through a short pad of
Celite, and the filtrate was evaporated in vacuo to give a thick,
oily compound. The IR of the oily compound was checked for above
mentioned carbonyl stretch frequency. Completion of reaction was
monitored by TLC using a thin layer silica gel plate; eluent: 40%
ethyl acetate in hexanes.
Step 6: Preparation of treprostinil (7)
##STR00035##
TABLE-US-00006 [0162] TABLE 6 Name MW Amount Mole Tricyclic ketone
(6) 486.65 0.0035 g 0.00006 Sodium hydroxide 40.0 0.030 g 0.00073
Sodium borohydride 37.8 0.004 g 0.00012 Methanol NA 5.0 ml NA Water
NA 1.0 ml NA HCl NA (10%) 4-5 ml NA
[0163] Procedure: A 200-mL round-bottom flask equipped with a
magnetic stirrer and stir bar was charged with a solution of
tricyclic ketone (6) (0.035 g) in methanol (5.0 mL). It was cooled
to -5.degree. C. and aqueous sodium hydroxide solution (0.030 g, 15
eq, dissolved in 1.0 mL water) was added while stirring. The
reaction mixture was stirred for 30 minutes and then sodium
borohydride (0.004 g in 1.0 mL water) was added and stirring was
continued at -5.degree. C. for 2 h. This was slowly allowed to warm
to room temperature and stirred overnight (.about.16 h). The
reaction mixture was quenched carefully by dropwise addition of 10%
hydrochloric acid (.about.4-5 mL) until pH 2-3. Then the mixture
was concentrated in vacuo and to this water (10 mL) and ethyl
acetate (10 mL) were added and stirred for 5-10 minutes. The
organic layer was separated and washed with brine (10 mL), dried
over sodium sulfate and concentrated in vacuo to obtain UT-15 (7)
as an off-white solid (0.021 g). The compound was characterized by
spectral data and HPLC. The .sup.1HNMR and HPLC of the samples were
compared with reference UT-15 and were identical; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 0.90 (t, 3H, 6 Hz), 1.05-1.78 (m,
13H), 2.85-2.85-2.98 (m, 1H), 2.03 2.12 (m, 1H), 2.21-2.32 (m, 1H),
2.45-2.53 (m, 1H), 2.61-2.81 (m, 3H), 3.52 (br s, 1H), 3.58-3.69
(m, 1H), 4.62 (s, 2H), 6.69 (d, 1H, J=8 Hz), 6.78 (d, 1H, J=8 Hz),
7.04 (dd, 1H, J=8 Hz).
Example 4
Preparation 2-Ally-3-(carbomethoxy)benzyloxybenzaldehyde
Reaction Scheme:
##STR00036##
[0164] Experimental:
Preparation of 2-Allyl-3-benzyloxybenzaldehyde (3)
TABLE-US-00007 [0165] TABLE 7 Name Mol Wt Amount mol
2-Allyl-3-hydroxybenzaldehyde 162.18 1.00 g 0.006 Benzyl
bromoacetate 229.08 1.53 g 0.006 Potassium carbonate 138.21 3.30 g
0.024 Acetone NA 20 mL NA
Experimental Procedure
[0166] To a solution of 2-allyl-3-hydroxybenzaldehyde (1) (1.00 g,
0.006 mol) in acetone (20 mL) was added powdered potassium
carbonate (3.30 g) and benzyl bromoacetate (2) (1.53 g, 0.006 mol).
The reaction mixture was stirred at 40.degree. C. (oil bath
temperature) for 5 h. The reaction mixture was checked by tlc (Note
1). The reaction was complete. The mixture was filtered, and the
filtrate was concentrated in vacuo to get crude viscous liquid. The
crude product was purified by silica gel column chromatography
using a mixture of ethyl acetate and hexanes (4-10%) to get
colorless viscous liquid (1.73 g, 88.7%). .sup.1H NMR (CDCl.sub.3,
300 Hz) 3.89 (m, 2H), 4.74 (s, 2H), 4.95-5.00 (m, 2H), 5.22 (s,
2H), 5.97-6.06 (m, 1H), 6.97 (m, 1H), 7.29-7.34 9m, 6H), 7.54 (m,
1H).
[0167] Note 1: Completion of the reaction was monitored by thin
layer chromatography (TLC) using a thin layer silica gel plate;
eluent: 10% ethyl acetate in hexanes.
Step 2: Preparation of chiral benzyl alkynol (4)
##STR00037##
TABLE-US-00008 [0168] TABLE 8 Name MW Amount mol Aldehyde 312.00
0.250 g 0.0008 Alkyne side 238.37 3.00 g 0.0025 chain (Sciv) Zinc
triflate 363.51 1.20 g 0.0030 (+)-N- 179.26 0.460 g 0.0025
Methylephedrine Triethylamine 101.19 0.810 g 0.0025 Toluene NA 10
mL NA
Procedure:
[0169] A 50-mL, two-necked, round-bottomed flask equipped with a
magnetic stirrer and stir bar was charged with zinc triflate (1.20
g, 0.0030 mol) and (+)-N-methylephedrine (0.460 g, 0.0025 mol) in
toluene (5 mL). To this mixture triethylamine was added (0.810 g,
0.0025 mol) and this gelatinous mixture was stirred at ambient
temperature for 1-2 h. To this mixture was then added a solution of
alkyne (3.00 g, 0.0025 mol) in toluene (4 mL), stirred at ambient
temperature for 15-30 minutes followed by addition of a solution of
aldehyde (0.250 g, 0.0008 mol in 1-2 mL toluene). Progress of the
reaction was monitored by TLC (Note 1). After stirring the mixture
at room temperature for 2 h, TLC indicated completion of reaction.
The reaction mixture was quenched by slow addition of water (10
mL). This was stirred for 5-10 minutes and organic layer containing
desired compound was separated. The aqueous layer was extracted
with ethyl acetate (10 mL). The combined organic layers were washed
with brine (10 mL), dried over anhydrous sodium sulfate, filtered
and the filtrate concentrated in vacuo to obtain a crude product.
The crude product was purified by column chromatography using
250-400 mesh silica gel. A solvent gradient of ethyl acetate in
hexanes (5-20%) was used to elute the product from the column. All
fractions containing the desired pure product were combined and
concentrated in vacuo to give pure chiral benzyl alkynol (370 mg,
84%). The structure was consistent with spectral data. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 0.84 (.tau., 3H), 1.24-1.75 (m, 17H),
2.24-2.30 (m, 2H), 3.43-3.47 (m, 1H), 3.65-3.84 (m, 2H), 3.86-3.87
(m, 1H), 4.63-4.67 (m, 3 h), 4.95-4.97 (m, 2H), 5.21 (s, 2H), 5.60
(m, 1H), 5.95-6.04 (m, 1H), 6.70 (m, 1H), 7.18-7.36 (m, 8H).
[0170] Note 1: Completion of the reaction was monitored by thin
layer chromatography (TLC) using a thin layer silica gel plate;
eluent: 20% ethyl acetate in hexanes.
Additional Embodiments
[0171] 1. A method of preparing a compound represented by the
following structural formula:
##STR00038##
[0172] comprising reacting a compound represented by the following
structural formula:
##STR00039##
[0173] with a compound represented by the following structural
formula:
##STR00040##
[0174] wherein: [0175] P.sub.1 is an alcohol protecting group;
[0176] R is --(CH.sub.2).sub.nX; [0177] X is H, phenyl, --CN,
--OR.sub.1 or COOR.sub.1; [0178] R.sub.1 is an alkyl, THP, TBDMS or
a unsubstituted or substituted benzyl group; and [0179] n is 1, 2
or 3. 2. The method of embodiment 1, wherein R is methyl. 3. The
method of embodiment 1, wherein R is
CH.sub.2CO.sub.2C.sub.2H.sub.5. 4. The method of embodiment 1,
wherein R is CH.sub.2CO.sub.2CH.sub.3. 5. The method of embodiment
1, wherein R is CH.sub.2CO.sub.2Bn. 6. The method of embodiment 1,
wherein P.sub.1 is tetrahydropyranyl (THP). 7. The method of
embodiment 1, wherein P.sub.1 is tert-butyldimethylsilyl (TBDMS),
tertiarybutyldiphenylsilyl (TBDPS), triethylsilyl (TES) or
triphenylmethyl (trityl group). 8. The method of embodiment 7,
wherein P.sub.1 is tert-butyldimethylsilyl (TBDMS). 9. The method
of embodiment 1, wherein the reaction is carried out in the
presence of chiral inducing agent. 10. The method of embodiment 9,
wherein the chiral inducing ligand is (+)-N-methylephederin. 11.
The method of embodiment 1, wherein the reaction is carried out in
the presence of a base and a zinc reagent. 12. The method of
embodiment 11, wherein the base is triethylamine. 13. The method of
embodiment 12, wherein the zinc reagent is zinc triflate. 14. A
method of preparing a compound represented by the following
structural formula:
##STR00041##
[0180] or a pharmaceutically acceptable salt thereof,
comprising:
[0181] reacting a compound represented by structural formula
(I):
##STR00042##
[0182] with a compound represented by structural formula (a):
##STR00043##
[0183] to form a compound represented by structural formula
(A):
##STR00044##
[0184] wherein: [0185] P.sub.1 is an alcohol protecting group;
[0186] R is --(CH.sub.2).sub.nX; [0187] X is H, phenyl, --CN,
--OR.sub.1 or COOR.sub.1; [0188] R.sub.1 is an alkyl group, THP,
TBDMS or a substituted or unsubstituted benzyl group; and [0189] n
is 1, 2 or 3. 15. The method of embodiment 14, further comprising:
[0190] (1) reacting the compound of structural formula (A) with an
alcohol protecting group to form a compound represented by
structural formula (II):
[0190] ##STR00045## [0191] (2) converting the compound of
structural formula (II) to a tricyclic compound represented by
structural formula (III):
[0191] ##STR00046## [0192] (3) hydrogenating the tricyclic compound
of structural formula (III) to form a hydrogenated tricyclic
compound represented by structural formula (IV):
[0192] ##STR00047## [0193] (4) reacting the compound of structural
formula (IV) with a reducing agent to form a compound represented
by structural formula (V):
[0193] ##STR00048## [0194] (5) deprotecting the compound of
structural formula (V) to form a compound represented by structural
formula (VI):
[0194] ##STR00049## [0195] (6) converting the compound represented
by structural formula (VI) to a compound represented by structural
formula (VII):
[0195] ##STR00050## [0196] (7) reacting the compound represented by
structural formula (VII) with X.sub.1(CH.sub.2).sub.mCN to form a
compound represented by structural formula (VIII):
##STR00051##
[0196] and [0197] (8) hydrolyzing the compound of Structural
Formula (VIII) to form the compound represented by Structural
Formula (IX), [0198] wherein: [0199] P.sub.2 is an alcohol
protecting group; [0200] m is 1, 2 or 3; and [0201] X.sub.1 is a
leaving group. 16. The method of embodiment 14, wherein R is
methyl. 17. The method of embodiment 14, wherein R is
CH.sub.2CO.sub.2C.sub.2H.sub.5. 18. The method of embodiment 14,
wherein P.sub.1 is tetrahydrofuranyl (THP). 19. The method of
embodiment 14, wherein the compound of structural formula (IX) is
tresprostinil represented by the following structural formula:
##STR00052##
[0201] 20. The method of embodiment 14, wherein the reaction of the
compound of structural formula (I) and the compound of structural
formula (a) is carried out in the presence of a chiral inducing
agent. 21. The method of embodiment 20, wherein the chiral inducing
agent is (+)-N-methylephederin. 22. The method of embodiment 20,
wherein the reaction is carried out in the presence of a base and a
zinc reagent. 23. The method of embodiment 22, wherein the base is
triethylamine. 24. The method of embodiment 22, wherein the zinc
reagent is zinc triflate. 25. The method of embodiment 15, wherein
P.sub.2 is tert-butyldimethylsilyl (TBDMS). 26. The method of
embodiment 15, wherein for step (2), the compound of structural
formula (II) is converted to the compound of structural formula
(III) through a cobalt-mediated cyclization reaction. 27. The
method of embodiment 26, wherein the cobalt-mediated cyclization
reaction is carried out in the presence of Co.sub.2(CO).sub.8. 28.
The method of embodiment 15, wherein the hydrogenation reaction of
step (3) is carried out in the presence of a base. 29. The method
of embodiment 28, wherein the base is K.sub.2CO.sub.3. 30. The
method of embodiment 15, wherein the reducing agent in step (4) is
NaBH.sub.4. 31. The method of embodiment 15, wherein for step (5),
the compound of structural formula (V) is deprotected in the
presence of an acid. 32. The method of embodiment 31, wherein the
acid is TsOH. 33. The method of embodiment 15, wherein for step
(6), the compound of structural formula (VI) is reacted with nBuLi
and Ph.sub.2PH. 34. The method of embodiment 15, wherein for step
(7), X.sub.1 is --Cl. 35. The method of embodiment 15, wherein for
step (8), the compound of structural formula (VIII) is hydrolyzed
in the presence of a base. 36. The method of embodiment 35, wherein
the base is NaOH. 37. The method of embodiment 15, wherein the
compound produced by the method is a sodium salt or a
diethanolamine salt of treprostinil. 38. The method of embodiment
15, wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, wherein R.sub.1
is an alkyl or a substituted or unsubstituted benzyl group. 39. The
method embodiment 38, further comprising: [0202] (a) reacting the
compound of structural formula (A) with a second alcohol protecting
group to form a compound represented by structural formula (4):
##STR00053##
[0202] and [0203] (b) converting the compound of structural formula
(4) to a tricyclic compound represented by structural formula
(5):
##STR00054##
[0203] 40. The method of embodiment 39, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl
(TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group). 41.
The method of embodiment 40, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS). 42. The method of embodiment 39,
wherein P.sub.1 is tetrahydrofuranyl (THP), benzyl,
2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl
(TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
43. The method of embodiment 42, wherein P.sub.1 is THP. 44. The
method of embodiment 39, wherein m is 1. 45. The method of
embodiment 39, wherein for the converting step (b), the compound of
structural formula (4) is converted to the compound of structural
formula (5) through a cobalt-mediated cyclization reaction. 46. The
method of embodiment 45, wherein the cobalt-mediated cyclization
reaction is carried out in the presence of Co.sub.2(CO).sub.8. 47.
The method of embodiment 39, wherein R.sub.1 is an alkyl group and
wherein the method further comprises: (c) hydrogenating the
tricyclic compound of structural formula (5) to form a hydrogenated
tricyclic compound represented by structural formula (6):
##STR00055##
and (d) converting the hydrogenated tricyclic compound represented
by structural formula (6) to a compound represented by structural
formula (IX):
##STR00056##
wherein said converting (d) accomplishes cleaving of the protective
group P.sub.1 and ester hydrolysis of R in a single pot. 48. The
method of embodiment 47, wherein the hydrogenation reaction of step
(c) is carried out in the presence of a base. 49. The method of
embodiment 48, wherein the base is K.sub.2CO.sub.3. 50. The method
of embodiment 47, wherein R.sub.1 is straight or branched C1-C5
alkyl. 51. The method of embodiment 50, wherein R.sub.1 is methyl.
52. The method of embodiment 39, wherein R.sub.1 is a substituted
or unsubstituted benzyl group and wherein the method further
comprises: [0204] (c') hydrogenating the tricyclic compound of
structural formula (5) to form a hydrogenated tricyclic compound
represented by structural formula (6'):
##STR00057##
[0204] and [0205] (d') converting the hydrogenated tricyclic
compound represented by structural formula (6') to a compound
represented by structural formula (IX):
##STR00058##
[0205] 53. The method of embodiment 52, wherein the hydrogenation
reaction of step (c) is carried out in the presence of a base. 54.
The method of embodiment 53, wherein the base is K.sub.2CO.sub.3.
55. The method of embodiment 52, wherein R.sub.1 is an
unsubstituted benzyl group. 56. The method of embodiment 14,
further comprising reacting compound represented by formula
(1):
##STR00059##
to form the compound represented by the structural formula
##STR00060##
57. A compound of formula (1):
##STR00061##
wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or 3, and
[0206] R.sub.1 is an alkyl group, THP, TBDMS or a substituted or
unsubstituted benzyl group. 58. The compound of embodiment 57,
wherein m is 1. 59. The compound of embodiment 57, wherein R.sub.1
is straight or branched C1-C5 alkyl. 60. The compound of embodiment
59, where R.sub.1 is methyl. 61. The compound of embodiment 57,
wherein R.sub.1 is unsubstituted benzyl. 62. A compound represented
by structural formula (A):
##STR00062##
[0206] wherein: [0207] P.sub.1 is an alcohol protecting group;
[0208] wherein R is (CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or
3, and [0209] R.sub.1 is an alkyl group or a substituted or
unsubstituted benzyl group. 63. The compound of embodiment 62,
wherein m is 1. 64. The compound of embodiment 62, wherein R.sub.1
is straight or branched C1-C5 alkyl. 65. The compound of embodiment
64, where R.sub.1 is methyl. 66. The compound of embodiment 62,
wherein R.sub.1 is unsubstituted benzyl. 67. The compound of
embodiment 62, wherein P.sub.1 is tetrahydrofuranyl (THP), benzyl,
2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl
(TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
68. The compound of embodiment 76, wherein P.sub.1 is THP. 69. A
compound represented by structural formula (4):
##STR00063##
[0209] wherein: [0210] each of P.sub.1 and P.sub.2 is an alcohol
protecting group; [0211] wherein R is
(CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or 3, and [0212] R.sub.1
is an alkyl group, or a substituted or unsubstituted benzyl group.
70. The compound of embodiment 69, wherein m is 1. 71. The compound
of embodiment 69, wherein R.sub.1 is straight or branched C1-C5
alkyl. 72. The compound of embodiment 71, where R.sub.1 is methyl.
73. The compound of embodiment 62, wherein R.sub.1 is unsubstituted
benzyl. 74. The compound of embodiment 62, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl
(TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group). 75.
The compound of embodiment 67, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS). 76. The compound of embodiment 69,
wherein P.sub.1 is tetrahydrofuranyl (THP), benzyl,
2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl
(TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
77. The compound of embodiment 76, wherein P.sub.1 is THP. 78. A
compound represented by structural formula (5):
##STR00064##
[0212] wherein: [0213] each of P.sub.1 and P.sub.2 is an alcohol
protecting group; [0214] wherein R is
(CH.sub.2).sub.mCO.sub.2R.sub.1, m is 1, 2 or 3, and [0215] R.sub.1
is an alkyl group, or a substituted or unsubstituted benzyl group.
79. The compound of embodiment 78, wherein m is 1. 80. The compound
of embodiment 78, wherein R.sub.1 is straight or branched C1-C5
alkyl. 81. The compound of embodiment 80, where R.sub.1 is methyl.
82. The compound of embodiment 78, wherein R.sub.1 is unsubstituted
benzyl. 83. The compound of embodiment 78, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS), tertiarybutyldiphenylsilyl
(TBDPS), triethylsilyl (TES) or triphenylmethyl (trityl group). 84.
The compound of embodiment 83, wherein P.sub.2 is
tert-butyldimethylsilyl (TBDMS). 85. The compound of embodiment 78,
wherein P.sub.1 is tetrahydrofuranyl (THP), benzyl,
2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl
(TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
86. The compound of embodiment 85, wherein P.sub.1 is THP. 87. A
compound represented by structural formula (6):
##STR00065##
[0215] wherein: [0216] P.sub.1 is an alcohol protecting group;
[0217] wherein m is 1, 2 or 3, and [0218] R.sub.1 is an alkyl
group, or hydrogen. 88. The compound of embodiment 87, wherein m is
1. 89. The compound of embodiment 87, wherein R.sub.1 is straight
or branched C1-C5 alkyl. 90. The compound of embodiment 89, where
R.sub.1 is methyl. 91. The compound of embodiment 87, wherein
R.sub.1 is unsubstituted benzyl. 92. The compound of embodiment 87,
wherein P.sub.1 is tetrahydrofuranyl (THP), benzyl,
2,4-dinitrobenzyl, methoxymethyl (MOM), tertiarybutyldimethylsilyl
(TBDMS), tertiarybutyldiphenylsilyl (TBDPS) or triethylsilyl (TES).
93. The compound of embodiment 92, wherein P.sub.1 is THP.
[0219] Although the foregoing refers to particular preferred
embodiments, it will be understood that the present invention is
not so limited. It will occur to those of ordinary skill in the art
that various modifications may be made to the disclosed embodiments
and that such modifications are intended to be within the scope of
the present invention.
[0220] All of the publications, patent applications and patents
cited in this specification are incorporated herein by reference in
their entirety.
* * * * *