U.S. patent application number 16/399682 was filed with the patent office on 2019-08-22 for salts of treprostinil.
This patent application is currently assigned to United Therapeutics Corporation. The applicant listed for this patent is United Therapeutics Corporation. Invention is credited to Hitesh Batra, Vijay Sharma, Sanmin Yang, Yi Zhang.
Application Number | 20190256449 16/399682 |
Document ID | / |
Family ID | 51530179 |
Filed Date | 2019-08-22 |
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United States Patent
Application |
20190256449 |
Kind Code |
A1 |
Batra; Hitesh ; et
al. |
August 22, 2019 |
SALTS OF TREPROSTINIL
Abstract
Provided are novel treprostinil salts as well as methods for
making treprostinil salts.
Inventors: |
Batra; Hitesh; (Herndon,
VA) ; Sharma; Vijay; (Olney, MD) ; Yang;
Sanmin; (Oakton, VA) ; Zhang; Yi; (Burke,
VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
United Therapeutics Corporation |
Silver Spring |
MD |
US |
|
|
Assignee: |
United Therapeutics
Corporation
Silver Spring
MD
|
Family ID: |
51530179 |
Appl. No.: |
16/399682 |
Filed: |
April 30, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15995372 |
Jun 1, 2018 |
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16399682 |
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15614801 |
Jun 6, 2017 |
9988334 |
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15995372 |
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15359941 |
Nov 23, 2016 |
9701611 |
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15614801 |
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14634131 |
Feb 27, 2015 |
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15359941 |
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14202618 |
Mar 10, 2014 |
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14634131 |
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61791015 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 59/72 20130101;
C07C 51/412 20130101; C07C 51/41 20130101; C07C 51/412 20130101;
A61P 9/12 20180101; C07C 59/72 20130101 |
International
Class: |
C07C 51/41 20060101
C07C051/41; C07C 59/72 20060101 C07C059/72 |
Claims
1-15. (canceled)
16. A salt of treprostinil, wherein the salt is a tromethamine
salt, an arginine salt, an L-Lysine salt, an N-methylglucamine
salt, a magnesium salt or an ammonium salt.
17. The salt of claim 16, wherein the salt is a tromethamine salt
of treprostinil.
18. The salt of claim 16, wherein the salt is an arginine salt of
treprostinil
19. The salt of claim 16, wherein the salt is an L-Lysine salt of
treprostinil.
20. The salt of claim 16, wherein the salt is an N-methylglucamine
salt of treprostinil.
21. The salt of claim 16, wherein the salt is a magnesium salt of
treprostinil.
22. The salt of claim 16, wherein the salt is an ammonium salt of
treprostinil
23. A pharmaceutical formulation comprising the salt of claim 16
and a pharmaceutically acceptable excipient.
24. The pharmaceutical formulation of claim 23, which is a solid
dose formulation.
25. A method of making a salt of treprostinil, comprising reacting
treprostinil with a base, which is selected from tromethamine,
arginine, L-Lysine, N-methylglucamine, choline hydroxide, calcium
hydroxide, magnesium hydroxide or ammonia to form a salt and
crystallizing the formed salt.
26. The method of claim 25, wherein a solvent for the reacting and
a solvent for said crystallizing is the same.
27. The method of claim 25, wherein a solvent for the reacting is
different from a solvent for said crystallizing.
28. The method of claim 25, wherein a solvent for the reacting
comprises an alcohol.
29. The method of claim 28, wherein the solvent for the reacting
further comprises water.
30. The method of claim 29, wherein the reacting comprises heating
a mixture comprising the solvent, the base and the treprostinil to
a temperature greater than 50.degree. C.
31. The method of claim 25, wherein the base is tromethamine.
32. The method of claim 30, wherein a solvent for the reacting
comprises isopropanol and methyl t-butyl ether.
33. The method of claim 25, wherein the base is arginine.
34. The method of claim 33, wherein a solvent for the reacting
comprises isopropanol and ethyl acetate.
35. The method of claim 33, wherein a solvent for the crystallizing
comprises ethanol.
36. The method of claim 25, wherein the base is L-lysine.
37. The method of claim 36, wherein a solvent for the reacting
comprises isopropanol and ethyl acetate.
38. The method of claim 25, wherein the base is
N-methylglucamine.
39. The method of claim 38, wherein a solvent for the reacting
comprises isopropanol, methyl t-butyl ether and hexanes.
40. The method of claim 25, wherein the base is magnesium
hydroxide.
41. The method of claim 40, wherein a solvent for the reacting
comprises ethanol, methyl t-butyl ether and hexanes.
42. The method of claim 25, wherein the base is ammonia.
43. The method of claim 42, wherein a solvent for the reacting
comprises isopropanol, methyl t-butyl ether and hexanes.
44. The method of claim 25, wherein the base is choline
hydroxide.
45. The method of claim 44, wherein a solvent for the reacting
comprises isopropanol and methyl t-butyl ether.
46. The method of claim 25, wherein the base is calcium
hydroxide.
47. The method of claim 46, wherein a solvent for the reacting
comprises ethanol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 15/995,372, filed Jun. 1, 2018, which is a Continuation of U.S.
application Ser. No. 15/614,801, filed Jun. 6, 2017, which is a
Continuation of U.S. application Ser. No. 15/359,941, filed Nov.
23, 2016, which is a Continuation of U.S. application Ser. No.
14/634,131, filed Feb. 27, 2015, which is a Continuation of U.S.
application Ser. No. 14/202,618, filed Mar. 10, 2014, now
abandoned, which claims the benefit under 35 U.S.C. .sctn. 119(e)
of U.S. Provisional Application No. 61/791,015, filed on Mar. 15,
2013, the contents of which are hereby incorporated by reference in
their entirety into the present disclosure.
BACKGROUND
[0002] Treprostinil, the active ingredient in Remodulin.RTM.,
Tyvaso.RTM. and Orenitram.TM., was first described in U.S. Pat. No.
4,306,075. Treprostinil, and other prostacyclin derivatives may be
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.
6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117; 8,461,393;
8,481,782; 8,242,305; 8,497,393; US patent applications nos.
2012-0190888 and 2012-0197041; PCT publication no.
WO2012/009816.
[0003] Various uses and/or various forms of treprostinil are
disclosed, for examples, in U.S. Pat. Nos. 5,153,222; 5,234,953;
6,521,212; 6,756,033; 6,803,386; 7,199,157; 6,054,486; 7,417,070;
7,384,978; 7,879,909; 8,563,614; 8,252,839; 8,536,363; 8,410,169;
8,232,316; 8,609,728; 8,350,079; 8,349,892; 7,999,007; 8,658,694;
8,653,137; US patent application publications nos. 2005/0165111;
2009/0036465; 2008/0200449; 2010-0076083; 2012-0216801;
2008/0280986; 2009-0124697; 2013-0261187; PCT publication no.
WO00/57701; US provisional applications nos. 61/781,303 filed Mar.
14, 2013 and 61/805,048 filed Mar. 25, 2013. The teachings of the
aforementioned references are incorporated by reference to show how
to practice the embodiments of the present invention.
[0004] The teachings of the aforementioned references are
incorporated by reference to show how to practice the embodiments
of the present invention. The methods described in these documents,
however, do not describe a feasible production method for producing
salts of treprostinil because the methods require the use of
excessive amounts of reagents and tedious chromatographic
purification techniques. Therefore, there is a need for an
economical, efficient and simplified method for preparing salts of
treprostinil.
[0005] In sum, treprostinil is of great importance from a medicinal
point of view. Therefore, a need exists for stable forms of
treprostinil which presents advantage in storage, shipment,
handling, and/or formulation, for example. From synthetic point of
view, the desired properties of UT-15 salts may include one or more
of the following properties: better aqueous solubility, higher
melting point, dense nature, and robust process.
SUMMARY
[0006] Certain embodiments of the present invention relate to
methods of preparing various salts of treprostinil.
[0007] One embodiment provides a treprostinil salt compound
according to the following formula:
##STR00001##
[0008] that may be optionally produced by a process comprising:
alkylating a starting compound of the formula:
##STR00002##
[0009] to form an O-alkylated compound that is not isolated;
followed by optional base hydrolysis and contacting the resulting
compound with a base or a base salt in situ; wherein X is a
pharmaceutically acceptable salt counterion and the treprostinil
salt is isolated as at least 98% pure. In one embodiment, the
treprostinil salt comprises Group IA or IIA metal. In another
embodiment, the treprostinil salt comprises K, Ca, Na, Ba, Li, Mg,
or Cs. In yet another embodiment, the treprostinil salt as isolated
is at least 98.5% pure; at least 98.8% pure; at least 99% pure; at
least 99.1% pure; at least 99.2% pure; at least 99.3% pure; at
least 99.4% pure; at least 99.5% pure; at least 99.6% pure; at
least 99.7% pure; at least 99.8% pure or at least 99.9% pure.
[0010] One embodiment provides a treprostinil salt compound
according to the following formula:
##STR00003##
[0011] wherein X is a pharmaceutically acceptable salt counterion
and the treprostinil salt is isolated preferably in a crystalline
form. Preferably, the isolated salt is at least 99% pure. In one
embodiment, the treprostinil salt comprises a Group IA or IIA
metal. In another embodiment, the treprostinil salt comprises K,
Ca, Na, Ba, Li, Mg or Cs. In yet another embodiment, the
treprostinil salt as isolated is at least 99.1% pure; at least
99.2% pure; at least 99.3% pure; at least 99.4% pure; at least
99.5% pure; at least 99.6% pure; at least 99.7% pure; at least
99.8% pure or at least 99.9% pure or at least 99.95% pure.
[0012] One embodiment provides a treprostinil salt compound
according to the following formula:
##STR00004##
[0013] that may be optionally produced by a process comprising:
alkylating a starting compound of the formula:
##STR00005##
[0014] to form an O-alkylated compound that is not isolated;
followed by hydrogenolysis and contacting the resulting compound
with a base or a base salt in situ; wherein X is a pharmaceutically
acceptable salt counterion and the treprostinil salt is isolated as
at least 98% pure. In one embodiment, the treprostinil salt
comprises a Group IA or IIA metal. In another embodiment, the
treprostinil salt comprises K, Ca, Na, Ba, Li, Mg or Cs. In yet
another embodiment, the treprostinil salt as isolated is at least
98.5% pure; at least 98.8% pure; at least 99% pure; at least 99.1%
pure; at least 99.2% pure; at least 99.3% pure; at least 99.4%
pure; at least 99.5% pure; at least 99.6% pure; at least 99.7%
pure; at least 99.8% pure or at least 99.9% pure.
[0015] Another embodiment provides a method for making a
treprostinil salt compound according to the following formula:
##STR00006##
[0016] comprising alkylating a starting compound of the
formula:
##STR00007##
[0017] to form an O-alkylated compound that is not isolated;
followed by optional base hydrolysis and contacting the resulting
compound with a base or a base salt in situ; wherein X is a
pharmaceutically acceptable salt counterion and the treprostinil
salt is isolated as at least 98% pure. In one embodiment, the
treprostinil salt comprises a Group IA or IIA metal. In another
embodiment, the treprostinil salt comprises K, Ca, Na, Ba, Li, Mg
or Cs. In yet another embodiment, the treprostinil salt as isolated
is at least 98.5% pure; at least 98.8% pure; at least 99% pure; at
least 99.1% pure; at least 99.2% pure; at least 99.3% pure; at
least 99.4% pure; at least 99.5% pure; at least 99.6% pure; at
least 99.7% pure; at least 99.8% pure or at least 99.9% pure.
[0018] Yet another embodiment provides a method for making a
treprostinil salt compound according to the following formula:
##STR00008##
[0019] comprising alkylating a starting compound of the
formula:
##STR00009##
[0020] to form an O-alkylated compound that is not isolated;
followed by hydrogenolysis and contacting the resulting compound
with a base or a base salt in situ; wherein X is a pharmaceutically
acceptable salt counterion and the treprostinil salt is isolated as
at least 98% pure. In one embodiment, the treprostinil salt
comprises a Group IA or IIA metal. In another embodiment, the
treprostinil salt comprises K, Ca, Na, Ba, Li, Mg or Cs. In yet
another embodiment, the treprostinil salt as isolated is at least
98.5% pure; at least 98.8% pure; at least 99% pure; at least 99.1%
pure; at least 99.2% pure; at least 99.3% pure; at least 99.4%
pure; at least 99.5% pure; at least 99.6% pure; at least 99.7%
pure; at least 99.8% pure or at least 99.9% pure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows embodiments of exemplary synthetic pathways
which result in treprostinil salt. In FIG. 1 each of R1 and R2 may
be independently selected from H or an alcohol protecting group,
such as H, TBDMS, THP, substituted or unsubstituted benzyl group.
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).
[0022] FIG. 2 is chart representing the relationship between yield
and the acetone/ethanol ratio.
[0023] FIG. 3 is chart representing the relationship between yield
and the ethyl acetate/ethanol ratio.
[0024] FIG. 4 is a flow chart for synthesis of salts of UT-15 and
UT-15 starting from triol.
DETAILED DESCRIPTION
[0025] Unless otherwise specified, "a" or "an" means "one or more".
The present invention relates to a novel monohydrate form of
treprostinil. Treprostinil is the active ingredient of
Remodulin.RTM., which has been approved by the U.S. FDA for the
treatment of Pulmonary Arterial Hypertension (PAH) in patients with
NYHA Class II, III and IV symptoms to diminish symptoms associated
with exercise using subcutaneous or intravenous administration.
Treprostinil is also the active ingredient in Tyvaso.RTM.
inhalation solution and Orenitram.TM. extended-release tablets.
[0026] Treprostinil's chemical name is
2-((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahyd-
ro-1H-cyclopenta[b]naphthalen-5-yloxy)acetic acid of the following
structure:
##STR00010##
[0027] Treprostinil (UT-15) is a benzindene prostacyclin containing
carboxylic acid functionality, various bases and base salts may
react with the acid functionality to form new salts of treprostinil
as shown in FIG. 1. In some embodiments, a hydroxide base, such as
alkaline metal hydroxide, may be reacted with treprostinil or a
synthetic intermediate of treprostinil to form a salt of
treprostinil. The hydroxide base may be, for example, an inorganic
base such as ammonium hydroxide, potassium hydroxide, calcium
hydroxide, sodium hydroxide, barium hydroxide, cesium hydroxide,
lithium hydroxide and magnesium hydroxide. The resulting salt may
be, for example, Potassium, Calcium, Sodium, Barium, Lithium,
Magnesium or Cesium salt. Yet in some embodiments, a base salt,
such as a carbonate, may be reacted with treprostinil or a
synthetic intermediate of treprostinil to form a salt of
treprostinil. The carbonate may be, for example, lithium carbonate,
potassium carbonate, sodium carbonate, cesium carbonate, calcium
carbonate, ammonium carbonate.
[0028] Additional salts may be used according to the processes
embodied herein, including for example, compounds with basic
groups, such as amine groups, basic salts include ammonium salts,
alkali metal salts (such as sodium, potassium and cesium salts) and
alkaline earth metal salts (such as magnesium, calcium and barium
salts).
[0029] One embodiment includes synthesis of a form new salt of
treprostinil by any of the following methods. In some embodiments,
the synthesis of salt may be a two step process starting from
compound of formula (1)
##STR00011##
wherein each of R1 and R2 may be independently selected from H or
an alcohol protecting group, such as H, TBDMS, THP, substituted or
unsubstituted benzyl group. 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). In many embodiments, the starting material may be benzindene
triol, i.e. compound of formula (1) with both R.sub.1 and R.sub.2
being H.
[0030] The first step may be alkylating compound of formula (1),
such benzindene triol, with an alkylating reagent. In some
embodiments, the alkylating reagent may have formula
##STR00012##
wherein X may be a halogen, such as Cl, Br or I; R may be CN or
COOR', wherein R' may be an alkyl group or substituted or
unsubstituted benzyl. 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. 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. In certain embodiments, the substituted benzyl
group may be para-methoxy benzyl or para-nitobenzyl.
[0031] As the result of the alkylating step, the following compound
of formula (2) may be formed:
##STR00013##
[0032] In some embodiments, the alkylating step may be performed in
the present of a base or a base salt, which may be, for example,
lithium carbonate, potassium carbonate, sodium carbonate, cesium
carbonate, calcium carbonate, ammonium carbonate, lithium
hydroxide, potassium hydroxide, magnesium hydroxide, barium
hydroxide, sodium hydroxide, calcium hydroxide.
[0033] In some embodiments, a solvent for the alkylating step may
be a polar aprotic solvent such as acetone, butanone,
tetrahydrofuran, tetriarybutyl methyl ether, ethyl acetate or a
combination thereof.
[0034] In some embodiments, the alkylating step may be performed
without a catalyst. Yet in some other embodiments, the alkylating
step may be performed in the presence of an alkylation catalyst,
which may be, for example, tetrabutyl ammonium bromide, potassium
iodide or sodium iodide.
[0035] In some embodiments, the second step may be hydrolysis of
the product of the alkylating step, such as compound of formula 2.
In certain embodiments, the hydrolysis may be followed by isolation
and/or crystallization of the product of hydrolysis from an
appropriate solvent. The product of hydrolysis may be treprostinil
salt
##STR00014##
or treprostinil as a free acid. The hydrolysis may be performed by
reacting the product of the alkylating step, such as compound of
formula 2, with a solution, which may comprise one or more of
hydroxide or a basic salt, such as carbonate. The hydroxide may be,
for example, ammonia hydroxide or a metal hydroxide. The metal
hydroxide may be, for example, a hydroxide of Group IA or Group IIA
solution. In certain embodiments, the metal hydroxide may be a
hydroxide of K, Ca, Mg, Ba, Cs, Li or Na. In some embodiments, the
basic salt may be, for example, a carbonate, such as lithium
carbonate, potassium carbonate, sodium carbonate, cesium carbonate,
calcium carbonate or ammonium carbonate.
[0036] In some cases, a solvent for the hydrolysis and a solvent
for the isolation and/or crystallization step may the same, but in
other cases, they may be different. Such solvent(s) may be an
organic solvent selected from ethanol, isopropyl alcohol, methanol,
acetone, ethyl acetate, hexanes, heptanes, isopropyl acetate or
combinations thereof.
[0037] In some embodiments, when R' is substituted or unsubstituted
benzyl group, the second step may be hydrogenalyzation of the
alkylation product, such as compound of formula 2. The
hydrogenalyzation of the alkylation product may be performed using
a hydrogenation catalyst, such as Pd catalyst on Carbon, in
presence of hydrogen. The hydrogenalyzation may be performed in an
alcoholic solvent, such as ethanol, methanol or isopropyl alcohol.
As the result of the hydrogenalyzation, the benzyl group may be
cleaved, thereby forming a "raw" mixture comprising treprostinil as
a free acid. In some embodiments, the "raw" mixture may be filtered
and evaporated to form solid treprostinil. Yet in some embodiments,
the raw mixture may be treated with a base, such as a hydroxide, or
a base salt, such as a carbonate, to form treprostinil salt, which
may be isolated and/or crystallized.
[0038] In some embodiments, if treprostinil as a free acid is
isolated as an intermediate, it may be then converted to its salt
form using an appropriate base or a base salt, which may be one or
more of hydroxide or carbonate, such as the ones discussed above.
In one embodiment, treprostinil may be formed in situ and contacted
with a base or a base salt to form a new salt of treprostinil. In
one embodiment, treprostinil is contacted with a base or a base
salt to form a new salt of treprostinil.
[0039] In some embodiments, the synthesis process may involve
passing through multiple, i.e. more than 1, stages for either or
both of treprostinil as a free acid and treprostinil salt. For
example, as the result of hydrolysis or hydrogenolysis treprostinil
as a free acid may be formed, which may be converted to a salt,
which then may converted back to treprostinil as a free acid, which
may have higher purity that the earlier treprostinil. Also, a
formed treprostinil salt may be converted to treprostinil as a free
acid, which may be converted to a new salt, which may be the same
or different from the original salt. Treprostinil or treprostinil
salt during each stage may or may not be isolated and/or
crystallized before a subsequent conversion.
[0040] FIG. 1 illustrates certain embodiments includes for
synthesis treprostinil salts. The synthesis of salt is a two or
three step process starting from benzindene triol: 1) the first
step is the O-alkylation of benzindene triol (1) with various
alkylating reagents as shown in FIG. 1; 2) the second step is the
optional hydrolysis of the nitrile intermediate (6) or ester
intermediates (7), (8) and (9) by using alkali metal bases followed
by isolation and crystallization of the salt from an appropriate
solvent such as one of ethanol, isopropyl alcohol, methanol,
acetone, ethyl acetate, hexanes, heptanes, isopropyl acetate or a
combination thereof. In some cases, the solvent system for both
reaction step and recrystallization step are same, but in other
cases they may be different; 3) if treprostinil as a free acid is
being isolated as an intermediate then convert it back to its salt
form using appropriate base as described in FIG. 1. In one
embodiment, treprostinil is formed in situ and contacted with the
base salt to form the new salt of treprostinil. In one embodiment,
treprostinil is contacted with the base salt to form the new salt
of treprostinil
[0041] The methods embodied herein allow for the formation of
treprostinil or treprostinil salt with reduced or simplified
purification. In one embodiment, treprostinil salt may be formed
from compound of formula 1, such as benzindene triol, without any
intermediate purification and/or isolation of treprostinil as a
free acid. In one embodiment, a composition comprising treprostinil
as a free acid and at least one impurity is contacted with the base
salt to form the new salt of treprostinil to form a substantially
pure new salt of treprostinil. In some embodiments, the new salt of
treprostinil is isolated as approximately 99.0, 99.1, 99.2, 99.3,
99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 99.95 percent pure.
[0042] The present salts may have an impurity profile different
than treprostinil materials produced by prior art methods. For
example, the present salts may have a lower concentration of one or
more of treprostinil impurities, such as any of 1AU90, 2AU90 and
3AU90, which are stereoisomers of treprostinil (UT-15); triol
(which could be a process impurity or a degradation product);
methyl ester and ethyl ester (process impurities), respectively;
and 750W93 and 751W93 (two dimers of treprostinil where the acid
group of one molecule esterifies with an alcohol on another
molecule of UT-15). In some embodiments, the new salt of
treprostinil does not comprise one or more of the listed impurities
in a detectable amount.
[0043] In some embodiments, the methods allow for the production of
a substantially pure salt of treprostinil from the triol (1)
without intermediate purification steps. The yield of the salt from
the triol (1) may be greater than 70%, or greater than 75%, or
greater than 80%, or greater than 85%, or greater than 90%.
[0044] Pathway 1, Pathway 2 or Pathway 3): Triol (1) may be
alkylated using various an alkylating reagent such as
##STR00015##
which may be halo acetonitrile (2), methyl bromoacetate (3), ethyl
bromoacetate (4) and benzyl bromoacetate (5) etc. in the presence
of a base or base salt, such as potassium carbonate, cesium
carbonate, lithium hydroxide etc. The O-alkylation of the phenolic
hydroxyl group of triol (1) may be carried out, for example, with
1-1.2 equivalents of the alkylating agent in presence of 1-3
equivalents of the base or a the base salt in a solvent, such as
acetone, butanone, tetrahydrofuran, tertiarybutyl methyl ether,
ethyl acetate. This O-alkylation may be carried with or without
catalyst such as tetrabutyl ammonium bromide, potassium iodide or
sodium iodide etc. Alkylation with haloacetonitrile (2) may provide
nitrile intermediate (6) which may be carried forward to hydrolysis
(step 6.fwdarw.10) without any further chromatographic
purification. Similarly, the O-alkylation of triol (1) may be
performed using an acetate, such as methyl bromoacetate (3), ethyl
bromoacetate (4) and benzyl bromoacetate (5) there by providing
ester in the form penultimate intermediates (7, 8 and 9) of
treprostinil. These ester intermediates (7, 8 and 9) may be carried
forward for hydrolysis without any further chromatographic
purification. The ester intermediate 9 bearing a benzyl group may
be hydrogenolysed using Palladium catalyst on carbon in presence of
hydrogen in an alcoholic solvent, such as ethanol, methanol, and
isopropyl alcohol. The whole process may be simplified by the fact
that after the benzyl group may cleave during the hydrogenation
condition (step 6.fwdarw.10) the alcoholic solution of reaction
mixture containing treprostinil (UT-15) in the form of a free acid
is filtered and evaporated to obtain treprostinil (UT-15) or this
may be treated with) 0.5 to 1 equivalent of a base or a base salt,
such as potassium hydroxide, calcium hydroxide, sodium hydroxide,
barium hydroxide, cesium hydroxide, lithium hydroxide. This
telescoping of the steps may lead to a process as shown in FIG.
4.
[0045] In the pathways 1, 2 and 3 the intermediates 6, 7, 8 and 9
after may provide treprostinil or its salt form (10) depending on
the base used during hydrolysis and its isolation during the
process. The pathways discussed above may be schematically
represented as follows:
[0046] Pathway 1:
##STR00016##
[0047] Experimental Steps may include: 1) O-Alkylate the triol and
carry the nitrile intermediate as such without purification to next
step for hydrolysis.
[0048] 2) Hydrolyze the ester intermediate and isolate as a salt
form.
[0049] 3) Crystallize to obtain the pure salt form.
[0050] Pathway 2:
##STR00017##
[0051] Experimental Steps may include 1) O-Alkylate the triol and
carry the ester intermediate as such without purification to next
step for hydrolysis. The ester intermediate "R" is not necessarily
limited to Me and Et, but rather any suitable ester known in the
art may be used. For example, R may be C.sub.1-C.sub.12 alkyl or a
C.sub.1-C.sub.6 alkyl. R may be optionally substituted by one or
more organic moieties that are compatible with the conditions of
the base hydrolysis step.
[0052] 2) Hydrolyze the ester intermediate and isolate as salt
form.
[0053] 3) Crystallize to obtain the pure salt form.
[0054] Pathway 3:
##STR00018##
Experimental Steps
[0055] 1) O-Alkylate the triol and carry the ester intermediate as
such without purification to next step for hydrogenolysis.
[0056] 2) Hydrogenolyze the ester intermediate and carry the
alcoholic solution, such as a methanol or ethanol solution, of acid
for treatment with base and form the salt. Or the ester may be
hydrolyzed with base to obtain the salt form of treprostinil. The
benzyl ether may be optionally substituted benzyl. Alternatively,
the benzyl may instead be an optionally substituted aryl
moiety.
[0057] 3) Crystallize to obtain the pure salt form.
[0058] In one embodiment, the salt of UT-15 demonstrates at least
one of the following improved properties: improved solubility,
desired biological activity, chemically-stable solid form and a
solid form that is stable in a solid-dose formulation.
[0059] The present application also provides a number of novel
treprostinil salts including potassium salt of treprostinil;
1-arginine salt of treprostinil, 1-lysine salt of treprostinil,
N-methylglucamine salt of treprostinil; choline salt of
treprostinil; magnesium salt of treprostinil; ammonium salt of
treprostinil; calcium salt of treprostinil and tromethamine salt of
treprostinil. In some embodiments, the salt of treprostinil may be
in a crystalline solid form. Yet in some embodiments, the salt of
treprostinil may in an amorphous solid form. Yet in some
embodiments, the salt of treprostinil may be a mixture of at least
one crystalline solid form and an amorphous solid form. A purity of
the salt in the solid form may be at least 98.0%; at least 98.5%;
at least 98.8%; at least 99%; at least 99.1%; at least 99.2%; at
least 99.3%; at least 99.4%; at least 99.5%; at least 99.6%; at
least 99.7%; at least 99.8%; or at least 99.9% or at least 99.95%.
The novel salts may be produced in large quantities, such as of at
least 20 g or at least 30 g or at least 40 g or at least 50 g or at
least 60 g or at least 70 g or at least 80 g or at least 90 g or at
least 100 g or at least 110 g or at least 120 g or at least 130 g
or at least 140 g or at least 150 g or at least 160 g or at least
170 g or at least 180 g or at least 190 g or at least 200 g.
[0060] One or more salt disclosed in this application may be used
for preparing a pharmaceutical formulation together with one or
more pharmaceutically acceptable excipient or additive. Suitable
additives or excipients include, but not limited to, sucrose,
lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol,
starch, agar, alginates, chitins, chitosans, pectins, tragacanth
gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or
semi-synthetic polymers or glycerides, methyl cellulose,
hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. In some
embodiments, while being dissolved in an appropriate solvent one or
more salts may be used for preparing a treprostinil formulation for
administering via subcutaneous, intravenous, oral or inhalation
route.
[0061] In some embodiments, one or more of the present salts in a
solid form may also be used for preparing a solid dosage oral form,
such as a powder, a granule, a tablet, a pellet, a pill, a capsule,
a gelcap, and a caplet, for oral administering. Optionally, the
oral dosage form may contain one or more other ingredients to aid
in administration, such as an inactive diluent, or a lubricant,
such as magnesium stearate, or a preservative, such as paraben or
sorbic acid, or an anti-oxidant, such as ascorbic acid, tocopherol
or cysteine, a disintegrating agent, a binders, a thickener, a
buffer, a sweetener, a flavoring agent or a perfuming agent.
Additionally, one or more of dyestuffs or pigments may be added for
identification. Tablets may be further treated with suitable
coating materials known in the art.
[0062] The invention is further illustrated by, though in no way
limited to, the following examples.
EXPERIMENTAL EXAMPLES
Example 1: Preparation of UT-15D-Potassium Salt
##STR00019##
[0064] Treprostinil potassium salt was made by adding treprostinil
(UT-15) to potassium hydroxide ethanol solution, followed by in two
different solvents: acetone or ethyl acetate. The experiment was
carried out in each solvent system (ethanol/acetone and
ethanol/ethyl acetate) with different ratio to find the best
condition to make the target compound. The results showed that
ethanol/ethyl acetate is a better solvent system than
ethanol/acetone, comparably. As can be seen in the table 1 and 2,
when the volume of acetone or ethyl acetate increased, the yield of
UT-15 potassium salt also increased accordingly, until the yield
reached to the peak at about 80%. Overall, the reaction condition
at ethanol/ethyl acetate ratio 1/10 is easy to work with, in term
of solvent boiling point, volume and yield of product (-80%). Based
on the results of the reaction in ethanol and ethyl acetate, an
experiment with a larger scale of .about.(40 g) was carried out.
The results confirmed the above findings. The melting point of the
UT-15 potassium salt was about 180.degree. C. in both
ethanol/acetone and ethanol ethyl acetate cases. The structure of
UT-15 potassium was confirmed by QC analytical data and other
spectral data.
Scheme 1 presents the flow chart of synthesis:
##STR00020##
Part One: Condition Study
[0065] In this part of the experiment, UT-15 potassium salt was
synthesized from two different solvent systems, ethanol/acetone and
ethanol/ethyl acetate. The experiment was carried out with
different ratios between ethanol and acetone, and between ethanol
and ethyl acetate, to find the best solvent condition for the
reaction.
a. Ethanol and Acetone
##STR00021##
[0066] To a clear solution of potassium hydroxide (1 eq.) in
ethanol (5 mL) in a round bottom flask, was added UT-I5 (1 eq.).
The mixture was stirred at room temperature for about 10 minutes
until a clear solution was obtained. Then acetone was added to the
ethanol solution while stirring. The stirring was stopped when
white solid started coming out from the solution. The mixture was
left at room temperature overnight. The solid was collected by
filtration. It was washed with acetone and then dried at 70.degree.
C. under vacuum for 4 hours. See the detail results in Table 1 and
in FIG. 2.
TABLE-US-00001 TABLE 1 Results of UT-15 potassium salt in ethanol
and acetone Lot # UT-15/KOH Eq. Acetone/EtOH M.P. .degree. C.
Yield, % D-1026-046 0.812 g/0.117 g 1.0/1.0 30 mL/5 mL (6/1)
178.5-179.5 56.1 D-1026-047 0.710 g/0.102 g 1.0/1.0 50 mL/5 mL
(10/1) 178.0-179.0 66.7 D-1026-049 0.853 g/0.122 g 1.0/1.0 75 mL/5
mL (15/1) 177.8-179.0 68.4 D-1026-051 0.723 g/0.104 g 1.0/1.0 100
mL/5 mL (20/1) 179.0-180.2 78.1 D-1026-085 0.730 g/0.105 g 1.0/1.0
125 mL/5 mL (25/1) 179.0-181.0 83.6
b. In Ethanol and Ethyl Acetate
##STR00022##
[0068] To a clear solution of potassium hydroxide (1 eq.) in
ethanol (5 mL) in a round bottom flask, was added UT-15 (1 eq.).
The mixture was stirred at room temperature for about 10 minutes
until a clear solution was obtained. Then ethyl acetate was added
to the ethanol solution while stirring. The stirring was stopped
when white solid started coming out from the solution. The mixture
was left at room temperature overnight. The solid was collected by
filtration. It was washed with ethyl acetate and then dried at
70.degree. C. under vacuum for 3 hours. See the detail results in
Table 2 and in FIG. 3.
TABLE-US-00002 TABLE 2 Results of UT-15 potassium salt in ethanol
and ethyl acetate Lot # UT-15/KOH Eq. EtOH/Ethyl Acetate M.P.
.degree. C. Yield, % D-1026-056 0.870 g/0.125 g 1.0/1.0 5 mL/25 mL
(1/5) 177.0-178.5 55.5 D-1026-059 0.799 g/0.115 g 1.0/1.0 5 mL/50
mL (1/10) 179.5-180.8 79.8 D-1026-062 0.771 g/0.111 g 1.0/1.0 5
mL/75 mL (1/15) 178.5-180.0 81.5 D-1026-086 1.100 g/0.158 g 1.0/1.0
5 mL/100 mL (1/20) 179.0-180.5 82.8 D-1026-087 0.998 g/0.143 g
1.0/1.0 5 mL/125 mL (1/25) 179.1-180.2 83.1
[0069] Part Two: Preparation of treprostinil (UT-15) potassium salt
(40 g scale)
##STR00023##
Table 3 provides materials used in the synthesis:
TABLE-US-00003 TABLE 3 Reagents MW Amount Mole Eq. UT-15 390.52
40.23 g 0.103 1.00 KOH 56.11 5.78 g 0.103 1.00 Ethanol -- 250 mL --
-- Ethyl Acetate -- 2500 mL -- --
To a 5-L round bottom flask, potassium hydroxide and ethanol were
added. It was stirred at room temperature until it was clear. To
the potassium ethanol solution, was added UT-15. The reaction
mixture was stirred at room temperature about 30 minutes until it
was clear. The mixture was then added ethyl acetate slowly while
stirring. The stirring was stopped when white solid started to come
out of the solution. The reaction mixture was allowed at room
temperature overnight. The solid was filtered, washed with ethyl
acetate (500 mL), dried at 70.degree. C. under vacuum for 6 hours
to give the product (35.12 g, 79.5%). Table 4 presents analytical
data.
TABLE-US-00004 TABLE 4 Melting point 180.0-182.degree. C. IR
Consistent with Structure .sup.1H NMR Consistent with Structure
.sup.13C NMR Consistent with Structure Purity (HPLC) 99.1%
Elemental Analysis Carbon Hydrogen 66.47% (Found) 7.75% (Found)
66.45% *Theory) 7.76% (Theory
Example 2: UT-15-Calcium Salt and Tromethamine Salts
[0070] Summary The objective of was to develop synthetic methods
for the synthesis of new salts of UT-15 and produce at least 50 g
of each salt. Present report describes the synthesis of two new
salts of UT-15: calcium and tromethamine salts. For these new
salts, analytical data: .sup.1H-NMR, 13C-NMR, IR, purity by HPLC,
DSC data, TGA data, water contents, specific rotation were
collected. Treprostinil (UT-I5) is benzindene prostacyclin
containing carboxylic acid moiety. Various bases (organic and
inorganic) were considered for the synthesis of new salts of UT-15.
Present report uses two bases: calcium hydroxide (inorganic base)
and tromethamine (organic base). Synthesis of these salts is a two
step process. First step involved the reaction of UT-IS (carboxylic
acid moiety) and base in appropriate solvent system, and second
step was the recrystallization of salt from appropriate solvent
system. Details of these steps are given in experimental
section.
Calcium Salt
##STR00024##
TABLE-US-00005 [0071] TABLE 5 Summary of materials used for
synthesis of UT-15 calcium salt. Name MW Amount Eq UT-15 390.52 60
g 1 Calcium hydroxide 74 5.40 0.5 EtOH -- 600 mL -- Water -- 1800
mL --
A 3000-mL, three-necked, round-bottom flask equipped with a
mechanical stirrer, thermometer and condenser was charged with
UT-15 (60 g), and ethanol (600 mL). Mixture was heated at
75-80.degree. C. until clear. To the clear solution calcium
hydroxide (5.40 g) was added in two portions. The reaction mixture
was stirred and heated to 70-80.degree. C. to obtain a clear
solution (.about.1 h). Water (1800 mL) was added slowly keeping the
temperature of solution at 75-80.degree. C. After complete addition
of water, the solution was allowed to cool to ambient temperature
overnight while stirring. The product was filtered, washed with
water and dried under vacuo for 1 h. The product was transferred
from the Buchner funnel to a glass and dried over night in a fume
hood. Finally the product was further dried under high vacuum at
50-55.degree. C. for 6 hours (50.2 g, mp. 154-160.degree. C.) Table
6 provides data for calcium salt.
TABLE-US-00006 TABLE 6 Structure ##STR00025## Amount 50 g Lot
number D-1055-077-1 Molecular formula C.sub.46H.sub.68CaO.sub.11 MW
837.12 Appearance Off white .sup.1H NMR Consistent with structure
.sup.13C NMR Consistent with structure Purity (HPLC) 98.9% Melting
point 154-160.degree. C.
Tromethamine Salt
##STR00026##
TABLE-US-00007 [0072] TABLE 7 Summary of materials used for
synthesis of UT-15 tromethanine salt. Name MW Amount Eq UT-15
390.52 54.55 g 1.00 Tromethanine 121.14 17.06 1.00 Isopropanol
(IPA) -- 330 mL -- MTBE -- 1500 mL -- Water -- 15 mL --
A 3000-mL, three-necked, round-bottom flask equipped with a
mechanical stirrer, thermometer and condenser was charged with
UT-15 (54.55 g), isopropanol (330 mL), and water (15 mL) and was
heated at 50-55.degree. C. until clear solution was obtained, then
tromethamine (17.06 g) was added. The reaction mixture was heated
to 60.degree. C. while stirring to obtain a clear solution. To his
clear solution methyl t-butyl ether (MTBE) was added slowly keeping
the temperature between 50-55.degree. C. After complete addition of
MTBE, the solution was allowed to cool to ambient temperature
overnight while stirring. The product was filtered, washed with
water and dried under vacuo for I h. The product was transferred
from the Buchner funnel to a glass tray and dried over night in a
fume hood. Finally the product was dried under high vacuum at
45-48.degree. C. for 4 hours (55.4 g, mp. 68-71.degree. C.). Table
8 provides data for tromethamine salt.
TABLE-US-00008 TABLE 8 Structure ##STR00027## Amount 50 g Lot
number D-1051-023 Molecular Formula C.sub.27H.sub.45NO.sub.8
Molecular Weight 511.66 Appearance White Solid .sup.1H NMR
Consistent with structure .sup.13C NMR Consistent with structure
Purity (HPLC) 99.93% Melting point 66-71.degree. C. Elemental
analysis Required C = 63.38, H = 8.86, N = 2.74 Required if as
monohydrate: C = 61.23, H = 8.94, N = 2.64 Found: C = 60.54, H =
8.98, N = 2.63 Water content 4.4% w/w Specific rotation
+32.4.degree. @ 589 nm and 25.degree. C. c = 1.0256 g/100 mL in
MeOH
Example 3: Synthesis of Alternate Treprostinil Salts
[0073] The objective was to develop new methods for the synthesis
of alternate salts of UT-15 and to produce at least 200 mg of each
salt for the dissolution studies. Total seven salts of UT-15 have
been prepared: 1. UT-15-L-Arginine salt 2. UT-15-L-Lysine salt 3.
UT-15-N-Methylglucamine salt 4. UT-15-Choline salt 5.
UT-15-Potassium salt 6. UT-15-Magnesium salt 7. UT-15-Ammonium salt
For all new UT-15 salts, analytical data: IH-NMR, 13C_NMR, IR,
purity by HPLC, DSC data, TGA data, water contents, specific
rotation were collected. Since UT-15 is benzindene prostacyclin
containing carboxylic acid, various bases were considered for the
synthesis of new salts of UT-15. This study used UT-15 with seven
bases, which include four organic bases and three inorganic bases.
Four organic bases were: L-arginine, L-lysine, N-methylglucamine,
and choline hydroxide. Other three inorganic bases include
potassium hydroxide, ammonia gas, and magnesium hydroxide.
Synthesis of salts was a two step process. First step was the
reaction of UT-15 (carboxylic acid) and base in appropriate solvent
system, and second step. was the recrystallization of salt from
appropriate solvent system. In some cases, the solvent system for
both reaction step and recrystallization step was same, but in
other cases it was different. Details of these steps were given in
experimental section. In few cases, the purpose of addition of
small amount of water was to avoid synthesis of ester of UT-15 with
alcoholic solvent, when the mixture was heated to greater than
50.degree. C.
Arginine Salt
##STR00028##
TABLE-US-00009 [0074] Name MW Amount Eq UT-15 390.52 4.50 g 1.00
L-Arginine 174.20 2.01 g 1.00 2-propanol -- 135 mL -- Water -- 10
mL -- Ethyl Acetate -- 250 mL --
[0075] Table 9 provides a summary of materials used in the
synthesis.
A 500-mL, two-necked, round-bottom flask equipped with a magnetic
stirrer, and a thermometer was charged with UT-15-L-Arginine salt
(17.01 g), ethanol (200 mL). The mixture was heated to
70-80.degree. C. while stirring. At this temperature, water (3 mL)
was added slowly to obtain a clear solution. After complete
addition of water, the solution was allowed to cool slowly to
ambient temperature. The product was isolated by filtration and
washed with ethanol. The product was transferred from the Buchner
funnel to a glass container for air-drying over night in a fume
hood. The product (lot D-1041-011) was dried under high vacuum at
70-75.degree. C. for 16 hours. Table 10 provides data for the
arginine salt.
TABLE-US-00010 TABLE 10 Structure ##STR00029## Lot number
D-1029-034 Molecular formula C.sub.29H.sub.48N.sub.4O.sub.7 MW
564.72 Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.12% Melting
Point 183-184.degree. C. Melting point (DSC) 182.04.degree. C. IR
Consistent with structure Elemental analysis Required: C = 61.68, H
= 8.57, N = 9.92 Found: C = 61.31, H = 8.55, N = 9.62 TGA Moisture
= 2.07, degradation beyond 200.degree. C. Water content 0.53% w/w
Specific rotation +35.8.degree. @ 589 nm and 25.degree. C.
L-Lysine Salt
##STR00030##
TABLE-US-00011 [0076] Name MW Amount Eq UT-15 390.52 4.50 g 1.00
L-lysine 146.19 1.685 g 1.00 2-propanol -- 108 mL -- Water -- 9 mL
-- Ethyl Acetate -- 225 mL --
[0077] Table 11 provides summary of materials used in the
synthesis
[0078] A 500-mL, two-necked, round-bottom flask equipped with a
magnetic stirrer, and a thermometer was charged with UT-15 (4.5 g),
2-propanol (108 mL), water (9 mL), and L-lysine (1.685 g). The
reaction mixture was stirred and heated to 70-80.degree. C. to
obtain a clear solution. At this temperature, ethyl acetate was
added slowly keeping the temperature of solution higher than
55.degree. C. After complete addition of ethyl acetate, the
solution was allowed to cool to 45.degree. C. during 1-2 hours,
then to 35.degree. C. for one hour, and then to 25.degree. C. for
an addition one hour. At ambient temperature, the product was
isolated by filtration; product was washed with ethyl acetate. The
product was transferred from Buchner funnel to a glass container
for air-drying over night in a fume hood. The product was dried
further under high vacuum at 50-55.degree. C. for 4-5 hours. Table
12 provides data for L-lysine salt.
TABLE-US-00012 Structure ##STR00031## Lot number D-1029-032
Molecular formula C.sub.29H.sub.48N.sub.2O.sub.7 MW 536.71
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.68% Melting
Point 106.degree. C. Melting point (DSC) 97.43.degree. C. IR
Consistent with structure Elemental analysis Required: C = 64.90, H
= 9.01, N = 5.22 Found: C = 60.90, H = 9.04, N = 4.85 TGA No weight
loss due to moisture; loss due to degradation beyond 200.degree. C.
Water content 6.7% w/w Specific rotation +36.3.degree. @ 589 nm and
25.degree. C.
N-Methylglucamine Salt
##STR00032##
TABLE-US-00013 [0079] Name MW Amount Eq UT-15 390.52 4.00 g 1.00
N-methylglucamine 146.19 2.00 g 1.00 2-propanol -- 60 mL -- Water
-- 0.8 mL -- MTBE -- 120 mL -- Hexanes -- 40 mL --
[0080] Table 13 provides a summary of materials used in the
experiments
[0081] A 500-mL, two-necked, round-bottom flask equipped with a
magnetic stirrer, and a thermometer was charged with UT-15 (4.0 g),
2-propanol (108 mL), water (0.8 mL), and N-methylglucamine (2.00
g). The reaction mixture was stirred and heated to 70-80.degree. C.
to obtain a clear solution. At this temperature, MTBE (120 mL) was
added slowly keeping the temperature of solution higher than
55.degree. C., followed by hexanes (40 mL). After complete addition
of MTBE and hexanes, the solution was allowed to cool to 45.degree.
C. during 1-2 hours, then to 35.degree. C. for one hour, and then
to 25.degree. C. for an additional 30 minutes. At ambient
temperature, the product was isolated by filtration and washed with
MTBE/hexanes (1:1). The product was transferred from Buchner funnel
to a glass container for air-drying over night in fume hood. The
product was dried further under vacuum at 50-55.degree. C. for 4
hours. Table 14 provides results for N-methylglucamine salt.
TABLE-US-00014 TABLE 14 Structure ##STR00033## Lot number
D-1029-036 Molecular formula C.sub.30H.sub.51NO.sub.10 MW 585.74
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.51% Melting
Point 82-83.degree. C. Melting point (DSC) 72.96.degree. C. IR
Consistent with structure Elemental analysis Required: C = 61.52, H
= 8.78, N = 2.39 Found: C = 59.77, H = 8.78, N = 2.34 TGA Weight
loss due to moisture up to 100.degree. C.; loss due to degradation
beyond 150.degree. C. Water content 3.3% w/w Specific rotation
+19.4.degree. @ 589 nm and 25.degree. C.
Mg Salt
##STR00034##
TABLE-US-00015 [0082] Name MW Amount Eq UT-15 390.52 5.75 g 1.00
Magnesium Hydroxide 58.33 0.439 g 0.5 Ethanol -- 172 mL -- Water --
55 mL -- MTBE -- 86 mL -- Hexanes -- 30 mL --
[0083] Table 15 provides summary of materials used in the
experiment.
[0084] A 500-mL, two-necked, round-bottom flask equipped with a
magnetic stirrer, and a thermometer was charged with UT-15 (5.75
g), ethanol (86 mL), water (55 mL), and magnesium hydroxide (439
mg). The reaction mixture was stirred and heated to 70-80.degree.
C. to obtain a clear solution. The solution was filtered to remove
any insoluble foreign particles. The filtrate was evaporated under
vacuum to give a gummy material. The gummy material was dissolved
in ethanol (86 mL) by heating to 70-80.degree. C. At this
temperature, MTBE (86 mL) was added slowly keeping the temperature
of solution higher than 55.degree. C., followed by hexanes (30 mL).
After complete addition of MTBE and hexanes, the solution was
allowed to cool to 45.degree. C. during 1-2 hours, then to ambient
temperature overnight. At ambient temperature, the product was
isolated by filtration and washed with MTBE. The product was
transferred from Buchner funnel to a glass container for air-drying
over night in fume hood. The product was dried further under vacuum
at 50-55.degree. C. for 4 hours. Table 16 provides data for the
magnesium salt.
TABLE-US-00016 TABLE 16 Structure ##STR00035## Lot number
D-1029-038 Molecular formula C.sub.23H.sub.33MgO.sub.5 MW 413.82
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.68% Melting
Point 80-81.5.degree. C. Melting point (DSC) 75.77.degree. C. IR
Consistent with structure Elemental analysis Required: C = 66.76, H
= 8.04 Found: C = 66.90, H = 8.29 TGA No weight loss due to
moisture; loss due to degradation beyond 250.degree. C. Water
content 13.1% w/w Specific rotation +44.degree. @ 589 nm and
25.degree. C.
Potassium Salt
##STR00036##
TABLE-US-00017 [0085] Name MW Amount Eq UT-15 390.52 4.00 g 1.00
Potassium Hydroxide 56.11 0.575 g 1.00 2-propanol -- 40 mL -- Water
-- One drop -- MTBE -- 25 mL -- Hexanes -- 85 mL --
[0086] Table 17 provides a summary of materials used in the
experiment.
A 500-mL, two-necked, round-bottom flask equipped with a magnetic
stirrer, and a thermometer was charged with UT-15 (4.00 g),
2-propanol (40 mL), water (one drop), and potassium hydroxide (575
mg). The reaction mixture was stirred and heated to 70-80.degree.
C. to obtain a clear solution. At this temperature, MTBE (25 mL)
was added slowly keeping the temperature of solution higher than
55.degree. C., followed by hexanes (85 mL). After complete addition
of MTBE and hexanes, the solution was allowed to cool to 45.degree.
C. during approximately 16 hours, then to ambient temperature. At
ambient temperature, the product was isolated by filtration and
washed with MTBE. The product was transferred from Buchner funnel
to a glass dish for air-drying overnight in fume hood. The product
(lot D-1 029-041) was dried further under vacuum at 50-55.degree.
C. for 4 hours. Table 18 provides data for the potassium salt.
TABLE-US-00018 TABLE 18 Structure ##STR00037## Lot number
D-1029-041 Molecular formula C.sub.23H.sub.33KO.sub.5 MW 428.61
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.39% Melting
Point 180-181.degree. C. Melting point (DSC) 177.37.degree. C. IR
Consistent with structure Elemental analysis Required: C = 64.45, H
= 7.76 Found: C = 64.42 H = 7.77 TGA No weight loss due to
moisture; loss due to degradation beyond 250.degree. C. Water
content 0.3% w/w Specific rotation +39.50.degree. @ 589 nm and
25.degree. C.
Ammonium Salt
##STR00038##
TABLE-US-00019 [0087] Name MW Amount Eq UT-15 390.52 4.00 g 1.00
Ammonia (gas) 17.03 -- -- 2-propanol -- 50 mL -- MTBE -- 75 mL --
Hexanes -- 75 mL --
[0088] Table 19 provides summary of materials used in the
experiment
[0089] A 500-mL, two-necked, round-bottom flask equipped with a
magnetic stirrer, and a thermometer was charged with UT-15 (4.00
g), 2-propanol (40 mL). The mixture was stirred and heated to
40-45.degree. C. to obtain a clear solution. Allow the temperature
of the solution to cool to 30-35.degree. C., and then bubble the
ammonia gas through the solution for 45 minutes. Ammonia gas inlet
was removed, and hexane (75 mL) was added and allowed the mixture
to stir overnight at ambient temperature. At ambient temperature,
the product was isolated by filtration; product was washed with
MTBE/hexanes (1:1). The product was transferred from Buchner funnel
to a glass dish for air-drying over night in fume hood. The product
(lot D-1029-043) was dried further under vacuum at 50-55.degree. C.
for 4 hours. Table 20 provides data for the ammonium salt.
TABLE-US-00020 TABLE 20 Structure ##STR00039## Lot number
D-1029-043 Molecular formula C.sub.23H.sub.37NO.sub.5 MW 407.55
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.52% Melting
Point 75-76.degree. C. Melting point (DSC) 69.42.degree. C. IR
Consistent with structure Elemental analysis Required: C = 67.78, H
= 9.15, N = 3.44 Found: C = 67.24, H = 9.13, N = 2.76 TGA 4% weight
loss due to moisture up to 100.degree. C.; continuous loss due to
degradation beyond 100.degree. C. Water content 4.6% w/w Specific
rotation +41.4.degree. @ 589 nm and 25.degree. C.
Choline Salt
##STR00040##
TABLE-US-00021 [0090] Name MW Amount Eq UT-15 390.52 4.00 g 1.00
Choline hydroxide 121.18 3.1 g 1.0 (45% wt, MeOH) 2-propanol -- 60
+ 90 mL -- MTBE -- 115 mL --
[0091] Table 21 provides summary of materials used in the
experiment.
[0092] A 500-mL, two-necked, round-bottom flask equipped with a
magnetic stirrer, and a thermometer was charged with UT-15 (4.50
g), 2-propanol (60 mL). The mixture was stirred and heated to
70-80.degree. C. to obtain a clear solution. To the solution was
added choline hydroxide (3.1 g) and stirred the mixture for short
period. The solvent was evaporated under vacuum to give a gummy
material. The gummy material was dissolved in 2-propanol (90 mL) by
heating to 70-80.degree. C. At this temperature, MTBE (115 mL) was
added slowly keeping the temperature of solution more than
55.degree. C. After complete addition of MTBE, the solution was
allowed to cool to 50.degree. C., then to 40.degree. C. and to
ambient temperature overnight. At ambient temperature, the product
was isolated by filtration; product was washed with MTBE/hexanes
(1:1). The product was transferred from Buchner funnel to a glass
container for air-drying over night in fume hood. The product was
dried further under vacuum at 50-55.degree. C. for 4 hours. Table
22 provides data for the choline salt.
TABLE-US-00022 TABLE 22 Structure ##STR00041## Lot number
D-1029-045 Molecular formula C.sub.28H.sub.47NO.sub.6 MW 493.68
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.36% Melting
Point 163-164.degree. C. Melting Point (DSC) pending .degree. C. IR
Consistent with structure Elemental analysis Required: C = 68.12, H
= 9.60, N = 2.84 Found: C = 67.76, H = 9.69, N = 2.83 TGA No weight
loss due to moisture; loss due to degradation beyond 150.degree. C.
Water content 0.9% w/w Specific rotation +34.2.degree. @ 589 nm and
25.degree. C.
Example 4: Synthesis of Potassium and L-Arginine Salts of
Treprostinil
[0093] This example reports to the synthesis of two salts,
potassium salt of UT-15 (UT-15D) and L-Arginine salt of UT-15. From
synthetic point of view, the desired properties of UT-15 salts may
include better aqueous solubility, higher melting point, dense
nature, and robust process. Two salts, UT-15D and UT-15-L-Arginine
possess the desired properties. Presently, potassium salt of UT-15
(UT-15D) was prepared using ethanol and ethyl acetate. Initially,
Arginine salt of UT-15 was prepared and recrystallized using
IPA/EtOAc/H.sub.20. Currently, IPA/H.sub.20 and EtOH/H.sub.20
solvent systems were used for recrystallization. The number of
solvents for recrystallization was reduced (three to two). Ethanol
is preferred over isopropanol for recrystallization, because
isopropanol was not removed completely from UT-15-L-Arginine at
temperature 70-75.degree. C., under high vacuum for more than 45
hours, whereas ethanol was removed within 16 hours under similar
conditions.
Potassium Salt
##STR00042##
TABLE-US-00023 [0094] Name MW Amount Eq Ratio UT-15 390.52 150.00 g
1.00 1.00 Potassium hydroxide 56.11 21.55 g 1.00 NA Ethyl acetate
NA 7500 mL NA 50.00 Ethanol NA 115 mL NA 5.00
Table 23 provides summary of materials used for the potassium salt
synthesis. A 12-L, three-necked, round-bottom flask equipped with a
mechanical stirrer was charged with potassium hydroxide (21.55 g),
ethanol (650 mL) at room temperature. The mixture was stirred to
obtain a clear solution. UT-15 (150.00 g, solid) was added in
portions to the solution of potassium hydroxide in ethanol at
ambient temperature. After complete addition of UT-15, the mixture
was stirred for 30 minutes to obtain a clear solution. At ambient
temperature, ethyl acetate (7500 m L) was added solution slowly
keeping the solution clear. The clear solution was allowed to stir
gently at ambient temperature for 3-4 hours to obtain a white
solid. The product was isolated by filtration and washed with ethyl
acetate. The product was transferred from the Buchner funnel to a
glass tray and air-dried in a fume-hood overnight. The product (lot
D-1029-171) was dried further under vacuum at 60-65.degree. C. for
7-8 hours to give UT-15D (133.0 g, yield 81%) Table 24 provides
data for potassium salt.
TABLE-US-00024 TABLE 24 Structure ##STR00043## Lot number
D-1029-166 Molecular C.sub.23H.sub.33KO.sub.5 formula MW 428.61
Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.9% Melting
Point 182-183.5.degree. C. IR Consistent with structure
L-Arginine Salt
##STR00044##
TABLE-US-00025 [0095] Name Amount Ratio Lot No. UT-15-L-Arginine
salt 17.01 1.00 D-1041-006 Ethanol (anhydrous) 200 mL 11.76
T-08-0186 Water 3 mL 0.176 Tap water
[0096] Table 25 provides summary of materials used in the
L-arginine salt synthesis.
A 500-mL, two-necked, round-bottom flask equipped with a magnetic
stirrer, and a thermometer was charged with UT-15-L-Arginine salt
(17.01 g), ethanol (200 mL). The mixture was heated to
70-80.degree. C. while stirring. At this temperature, water (3 mL)
was added slowly to obtain a clear solution. After complete
addition of water, the solution was allowed to cool slowly to
ambient temperature. The product was isolated by filtration and
washed with ethanol. The product was transferred from the Buchner
funnel to a glass container for air-drying over night in a fume
hood. The product (lot D-1041-011) was dried under high vacuum at
70-75.degree. C. for 16 hours. Table 26 provides data for the
L-arginine salt.
TABLE-US-00026 TABLE 26 Structure ##STR00045## Lot number
D-1041-011 Molecular formula C.sub.29H.sub.48N.sub.4O.sub.7 MW
564.72 Appearance White Solid .sup.1H-NMR Consistent with structure
.sup.13C-NMR Consistent with structure Purity (HPLC) 99.87% Purity
(HPLC, assay) 100.15% Melting Point 184-185.degree. C. Elemental
analysis Required: C = 61.68, H = 8.57, N = 9.92 Found: C = 61.52,
H = 8.71, N = 9.79 Specific rotation +36.6.degree. @ 589 nm and
25.2.degree. C., and C = 1.0230
[0097] 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.
[0098] All of the publications, patent applications and patents
cited in this specification are incorporated herein by reference in
their entirety.
* * * * *