U.S. patent application number 13/901170 was filed with the patent office on 2013-09-26 for process for preparing prostaglandin derivatives.
This patent application is currently assigned to YONSUNG FINE CHEMICAL CO., LTD.. The applicant listed for this patent is YONSUNG FINE CHEMICAL CO., LTD.. Invention is credited to Jae Eun JOO, Yong Hyun KIM, Kee Young LEE, Changyoung OH.
Application Number | 20130253218 13/901170 |
Document ID | / |
Family ID | 42728959 |
Filed Date | 2013-09-26 |
United States Patent
Application |
20130253218 |
Kind Code |
A1 |
OH; Changyoung ; et
al. |
September 26, 2013 |
PROCESS FOR PREPARING PROSTAGLANDIN DERIVATIVES
Abstract
The present invention relates to a process for preparing a
prostaglandin derivative and an intermediate therefor. In
accordance with the present invention, the prostaglandin F (PGF)
derivative can be efficiently prepared with high purity by removing
the protecting group of a protected prostaglandin E (PGE)
derivative obtained from conjugate addition and then
stereoselectively reducing the ketone group on the cyclopentanone
ring of the PGE derivative.
Inventors: |
OH; Changyoung; (Yongin-si,
KR) ; LEE; Kee Young; (Seoul, KR) ; KIM; Yong
Hyun; (Suwon-si, KR) ; JOO; Jae Eun;
(Suwon-si, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
YONSUNG FINE CHEMICAL CO., LTD. |
Gyeonggi-do |
|
KR |
|
|
Assignee: |
YONSUNG FINE CHEMICAL CO.,
LTD.
Gyeonggi-do
KR
|
Family ID: |
42728959 |
Appl. No.: |
13/901170 |
Filed: |
May 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13255417 |
Dec 20, 2011 |
|
|
|
PCT/KR2010/001529 |
Mar 11, 2010 |
|
|
|
13901170 |
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Current U.S.
Class: |
560/75 ;
564/171 |
Current CPC
Class: |
C07C 405/00 20130101;
Y02P 20/55 20151101; C07C 69/734 20130101; C07C 2601/08 20170501;
C07C 233/11 20130101 |
Class at
Publication: |
560/75 ;
564/171 |
International
Class: |
C07C 233/11 20060101
C07C233/11; C07C 69/734 20060101 C07C069/734 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 2009 |
KR |
10-2009-0020920 |
Claims
1. Travoprost having a purity of 99.5% or more.
2. Bimatoprost having a purity of 99.5% or more.
3. A compound of the following formula (8): ##STR00018##
4. A compound of the following formula (9): ##STR00019##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 13/255,417 filed Dec. 20, 2011, which is a National Stage of
International Application No. PCT/KR2010/001529 filed Mar. 11,
2010, claiming priority based on Korean Patent Application No.
10-2009-0020920, filed Mar. 11, 2009, the contents of all of which
are incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to a process for efficiently
preparing a prostaglandin derivative with high purity and an
intermediate therefor.
BACKGROUND ART
[0003] Prostaglandin derivatives, particularly travoprost,
bimatoprost and latanoprost of the following formula (2) have been
extensively used due to their clinical effects such as reducing
intraocular pressure and promoting hair and eyelash growth.
##STR00001##
[0004] The prostaglandin derivatives have been conventionally
prepared through many synthetic steps in poor yields. The most
common commercial processes use Corey lactone as a starting
material to produce the prostaglandin derivatives, as shown in the
following Reaction Scheme 1 (see E. J. Corey et al., J. Amer. Chem.
Soc., 91, 5675-5677, 1969). However, Corey lactone is expensive and
the processes require a chromatographic separation for removing
.beta.-OH which is produced as a by-product on the reduction of
15-ketone group into .alpha.-OH after the introduction of
.omega.-chain. Therefore, the processes are unsuitable for
large-scale production of the prostaglandin derivatives in terms of
poor yields and high costs. The .beta.-OH produced as a by-product
may be reduced by using a chiral borane compound as a
stereoselective reducing agent, but the chiral borane compound is
also very expensive.
##STR00002##
[0005] To overcome the above disadvantages, it was suggested to
prepare the prostaglandin derivatives by conjugate addition of
.omega.-chain including .alpha.-OH to cyclopentenone derivatives
having .alpha.-side chain, as shown in the following Reaction
Scheme 2. In particular, a process developed by Lipshuts et al. can
stereoselectively introduce .omega.-chain by using higher order
mixed organocuprate (see U.S. Pat. Nos. 4,785,124, 4,904,820,
4,952,710 and 5,055,604, and WO 02/090324).
##STR00003##
[0006] Such process requires that, in order to synthesize
prostaglandin F (PGF) derivatives, the ketone group on the
cyclopentanone ring of the prostaglandin E (PGE) derivatives
obtained from the conjugate addition should be stereoselectively
reduced to .alpha.-OH. The use of sodium borohydride (NaBH.sub.4)
as a reducing agent gives the PGF derivatives in the form of a 6:4
mixture of .alpha.-OH and .beta.-OH, and the use of a bulky hydride
such as L-selectride, N-selectride, K-selectride and LS-selectride
gives the PGF derivatives in increased selectivity of 9:1
(.alpha.:.beta. ratio). However, a significant amount of .beta.-OH
should be still removed by using a difficult method causing large
yield loss.
[0007] Therefore, there has been a need to develop a process for
more stereoselectively reducing the ketone group on the
cyclopentanone ring of the prostaglandin E derivatives.
DISCLOSURE
Technical Problem
[0008] The present inventors have endeavored to overcome the above
problems and found that a highly pure PGF derivative having little
or no .beta.-OH can be efficiently prepared by removing the
protecting group of the prostaglandin E (PGE) derivative obtained
from conjugate addition and then stereoselectively reducing the
ketone group on the cyclopentanone ring.
[0009] An object of the present invention is, therefore, to provide
a process for efficiently preparing a PGF derivative with high
purity.
[0010] Another object of the present invention is to provide a
novel intermediate used in said process.
Technical Solution
[0011] One aspect of the present invention relates to a process for
preparing a prostaglandin F (PGF) derivative of the following
formula (1), which comprises the steps of:
[0012] (i) removing the hydroxy protecting group of a protected
prostaglandin E (PGE) derivative of the following formula (5) to
give a prostaglandin E (PGE) derivative of the following formula
(6); and
[0013] (ii) stereoselectively reducing the ketone group on the
cyclopentanone ring of the compound of the following formula
(6):
##STR00004##
wherein,
[0014] is a single or double bond;
[0015] X is O or NH;
[0016] Y is .alpha.-OH or difluoro, preferably .alpha.-OH;
[0017] Y' is .alpha.-OPG or difluoro, preferably .alpha.-OPG;
[0018] Z is CH.sub.2, O or S, preferably CH.sub.2 or O;
[0019] R is H or C.sub.10-C.sub.5 alkyl, preferably
C.sub.10-C.sub.5 alkyl;
[0020] R' is C.sub.10-C.sub.5 alkyl, C.sub.3-C.sub.7 cycloalkyl or
aryl, preferably phenyl optionally substituted by C.sub.10-C.sub.5
haloalkyl or halogen, more preferably CF.sub.3, Cl or F, most
preferably CF.sub.3; and
[0021] PG is a hydroxy protecting group, preferably
tetrahydropyranyl, trimethylsilyl, triethylsilyl or
t-butyldimethylsilyl, more preferably triethylsilyl.
[0022] The term "C.sub.1-C.sub.5 alkyl" as used herein means a
straight or branched hydrocarbon having 1 to 5 carbon atoms, which
includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, n-pentyl, etc., but is not limited thereto.
[0023] The term "C.sub.3-C.sub.7 cycloalkyl" as used herein means a
cyclic hydrocarbon having 3 to 7 carbon atoms, which includes
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but is not
limited thereto.
[0024] The term "aryl" as used herein includes all of aromatic
group, heteroaromatic group and partially reduced derivatives
thereof. The aromatic group means a 5 to 15-membered simple or
fused ring. The heteroaromatic group means an aromatic group
containing at least one atom selected from oxygen, sulfur and
nitrogen. Examples of the aryl include phenyl, naphthyl, pyridinyl,
furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl,
thiazolyl, tetrahydronaphthyl, etc., but are not limited
thereto.
[0025] The C.sub.10-C.sub.5 alkyl, C.sub.3-C.sub.7 cycloalkyl and
aryl may have one or more hydrogens substituted by C.sub.10-C.sub.5
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.10-C.sub.5 haloalkyl,
C.sub.10-C.sub.5 alkoxy, C.sub.10-C.sub.5 thioalkoxy, aryl, acyl,
hydroxy, thio, halogen, amino, alkoxycarbonyl, carboxyl, carbamoyl,
cyano, nitro, etc.
[0026] The process of the present invention is, hereinafter,
described in more detail referring to the following Reaction Scheme
3.
##STR00005##
Step 1: Preparation of Prostaglandin E (PGE) Derivative of Formula
(6)
[0027] The prostaglandin E (PGE) derivative of formula (6) is
prepared by removing the hydroxy protecting group of the protected
PGE derivative of formula (5).
[0028] The deprotection may be carried out under an acidic
condition. Particularly, silyl protecting groups may be deprotected
by using various fluoride compounds.
[0029] The acidic condition for silyl protecting groups may be
provided by the use of d-HCl, an aqueous NaHSO.sub.4 solution,
pyridinium p-toluensulfonate (PPTS), etc. Preferably, PPTS is used
in a catalytic amount in a mixture of acetone and water. Examples
of the fluoride compounds include tetrabutylammonium fluoride
(Bu.sub.4N.sup.+F.sup.-), hydrogen fluoride-pyridine (HF-pyridine),
fluorosilicic acid (H.sub.2SiF.sub.6), etc., but are not limited
thereto.
[0030] The compound of formula (5) having a carbon-carbon double
bond at 13 and 14 position may be prepared by converting an alkenyl
tin compound of the following formula (3) to its cuprate, followed
by conjugate addition to a cyclopentenone compound of the following
formula (4), according to a known method (see J. Am. Chem. Soc.
1988, 110, 2641-2643).
##STR00006##
[0031] Preferably, the alkenyl tin compound of formula (3) is added
to a solution of Me.sub.2Cu(CN)Li.sub.2 and converted to a higher
order mixed cuprate of the following formula (7), which is
subjected to conjugate addition to the cyclopentenone compound of
formula (4).
##STR00007##
[0032] The above reaction is preferably carried out in a mixture of
tetrahydrofuran (THF) and hexane or a mixture of THF and ether,
most preferably a mixture of THF and diethyl ether, as a
solvent.
[0033] The conjugate addition is preferably carried out in a low
temperature of -60.degree. C. or less.
[0034] The alkenyl tin compound of formula (3) may be prepared by
reacting a w-chain precursor containing a terminal acetylene group
with Bu.sub.3SnH, according to a known method (see J. Am. Chem.
Soc. 1988, 110, 2641-2643).
[0035] Meanwhile, the compound of formula (5) having a
carbon-carbon single bond at 13 and 14 position may be prepared by
the method disclosed in WO 02/090324.
Step 2: Preparation of Prostaglandin F (PGF) Derivative of Formula
(1)
[0036] The prostaglandin F (PGF) derivative of formula (1) is
prepared by stereoselectively reducing the ketone group on the
cyclopentanone ring of the compound of formula (6).
[0037] A reducing agent used in the present invention includes
sodium borohydride (NaBH.sub.4), L-selectride, N-selectride,
K-selectride, LS-selectride, 2,6-di-tert-butyl-4-methyl phenol and
diisobutyl aluminium hydride (DIBAL), etc., but is not limited
thereto. Preferably, 2,6-di-tert-butyl-4-methyl phenol and DIBAL
are used.
[0038] The use of 2,6-di-tert-butyl-4-methyl phenol and DIBAL leads
to stereoselective preparation of .alpha.-OH compound having no
.beta.-OH. Generally, the reduction is carried out by reacting
2,6-di-tert-butyl-4-methyl phenol in an amount of 2 to 10
equivalents, preferably 5 equivalents with DIBAL in an amount of 2
to 5 equivalents, preferably 4 equivalents in toluene as a solvent
at -10 to 10.degree. C., preferably 0.degree. C. for 1 to 2 hours,
preferably 1 hour; lowering the temperature of the reaction
solution to -70.degree. C.; adding the compound of formula (6)
thereto, followed by stirring for 1 to 3 hours, preferably 2 hours;
raising the temperature of the reaction solution to -40 to
-20.degree. C., preferably -30.degree. C.; and stirring the
reaction solution for 3 to 6 hours, preferably 4 hours.
[0039] Alternatively, the prostaglandin F (PGF) derivative of
formula (1) wherein X is NH may be prepared by reacting the PGF
derivative of formula (1) wherein X is O and R is methyl, with
RNH.sub.2.
[0040] The above reaction is preferably carried out at room
temperature.
[0041] Examples of the prostaglandin F (PGF) derivative of formula
(1) prepared by the present process include travoprost, bimatoprost
and latanoprost, which are widely used due to their clinical
effects such as reducing intraocular pressure and promoting hair
and eyelash growth. According to the present invention, travoprost,
bimatoprost and latanoprost can be prepared with high purity of
99.5% or more by further comprising the step of purifying them by
HPLC using a mixture of hydrocarbon and alcohol, preferably a
mixture of n-hexane and anhydrous ethanol or a mixture of n-heptane
and anhydrous ethanol, or a mixture of dichloromethane and alcohol,
preferably a mixture of dichloromethane and isopropanol.
[0042] Another aspect of the present invention relates to a
compound of the following formula (8), which is an intermediate of
travoprost, and a compound of formula (9), which is an intermediate
of bimatoprost.
##STR00008##
Advantageous Effects
[0043] In accordance with the present invention, the prostaglandin
F (PGF) derivative can be efficiently prepared with high purity by
removing the protecting group of the protected prostaglandin E
(PGE) derivative obtained from conjugate addition and then
stereoselectively reducing the ketone group on the cyclopentanone
ring of the PGE derivative. Particularly, the .alpha.-OH compound
having no .beta.-OH can be stereoselectively prepared using
2,6-di-tert-butyl-4-methyl phenol and diisobutyl aluminum hydride
(DIBAL) as a reducing agent.
BEST MODE
[0044] The present invention is further illustrated by the
following examples, which are not to be construed to limit the
scope of the invention.
Example 1
Preparation of Compound (8)
##STR00009##
[0046] Copper cyanide (30 g) was dissolved in THF (680 ml),
followed by cooling to 0.degree. C., and methyllithium (1.6 M
diethyl ether, 445 ml) was added dropwise thereto. The resulting
reaction solution was stirred for 10 to 20 minutes, and compound
(3-I) (215 g) dissolved in THF (200 ml) was added thereto. The
resulting reaction solution was stirred for 1.5 to 2 hours,
followed by cooling to -70.degree. C., and compound (4-I) (90 g)
dissolved in THF (680 ml) was rapidly added thereto, and then the
temperature of the reaction solution was slowly raised to
-45.degree. C. After the reaction was completed, the resulting
reaction solution was added to a mixture of aqueous ammonium
chloride solution/ammonia water (9:1, 1.8 L) and diethyl ether (2
L), followed by stirring at room temperature for 1 to 2 hours. The
organic layer was separated, dried over sodium sulfate (1 kg),
filtered and concentrated. The resulting residue was subjected to
chromatography (eluent: n-hexane:ethyl acetate=10:1) to give the
target compound (127 g, Yield: 75%).
Example 2
Preparation of Compound (6-I)
##STR00010##
[0048] Pyridinium p-toluensulfonate (PPTS, 2.3 g) was added to
compound (8) (127 g) dissolved in a mixture of acetone (1.2 L) and
water (0.25 L), followed by stirring at room temperature for 12
hours. After the reaction was completed, the resulting reaction
solution was concentrated under vacuum, and ethyl acetate (1.5 L)
and water (1 L) were added thereto, followed by stirring. The
organic layer was separated, dried over sodium sulfate (1 kg),
filtered and concentrated. The resulting residue was subjected to
chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the
target compound (78 g, Yield: 89%).
Example 3
Preparation of Travoprost
##STR00011##
[0050] 2,6-Di-tert-butyl-4-methyl phenol (172 g) was dissolved in
toluene (2 L), followed by cooling to 0.degree. C., and DIBAL (1.0
M toluene, 625 ml) was added dropwise thereto for 1 hour. The
resulting reaction solution was cooled to -70.degree. C., and
compound (6-I) (78 g) dissolved in toluene (0.5 L) was added
dropwise thereto. The resulting reaction solution was stirred for
about 2 hours, and its temperature was slowly raised to -40 to
-20.degree. C., followed by stirring for 4 hours. After the
reaction was completed, an aqueous 2N hydrochloric acid solution (1
L) was added. The organic layer was separated, dried over sodium
sulfate (1 kg), filtered and concentrated. The resulting residue
was subjected to chromatography (eluent: n-hexane:ethyl
acetate=1:5) to give travoprost (Purity: 96% or more). The obtained
compound was subjected to preparative HPLC (eluent:
dichloromethane:isopropanol=90:10) to give highly pure travoprost
(50 g, Purity: 99.5% or more, Yield: 63%).
Example 4
Preparation of Compound (9)
##STR00012##
[0052] Copper cyanide (98 g) was dissolved in THF (2.2 L), followed
by cooling to 0.degree. C., and methyllithium (1.6 M diethyl ether,
1.44 L) was added dropwise thereto. The resulting reaction solution
was stirred for 10 to 20 minutes, and compound (3-II) (598 g)
dissolved in THF (1.4 L) was added thereto. The resulting reaction
solution was stirred for 1.5 to 2 hours, followed by cooling to
-70.degree. C., and compound (4-II) (270 g) dissolved in THF (2.2
L) was added thereto for 15 minutes, and then the temperature of
the reaction solution was slowly raised to -45.degree. C. After the
reaction was completed, the resulting reaction solution was added
to a mixture of aqueous ammonium chloride solution/ammonia water
(9:1, 7.0 L) and diethyl ether (3.5 L), followed by stirring at
room temperature for 1 to 2 hours. The organic layer was separated,
dried over sodium sulfate (1 kg), filtered and concentrated. The
resulting residue was subjected to chromatography (eluent:
n-hexane:ethyl acetate=10:1) to give the target compound (420 g,
Yield: 88%).
Example 5
Preparation of Compound (6-II)
##STR00013##
[0054] Pyridinium p-toluensulfonate (PPTS, 8.8 g) was added to
compound (9) (420 g) dissolved in a mixture of acetone (4.3 L) and
water (0.83 L), followed by stirring at room temperature for 12
hours. After the reaction was completed, the resulting reaction
solution was concentrated under vacuum, and ethyl acetate (5.0 L)
and water (2.0 L) were added thereto, followed by stirring. The
organic layer was separated, dried over sodium sulfate (1 kg),
filtered and concentrated. The resulting residue was subjected to
chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the
target compound (205 g, Yield: 76%).
Example 6
Preparation of Compound (1-I)
##STR00014##
[0056] 2,6-Di-tert-butyl-4-methyl phenol (560 g) was dissolved in
toluene (6.5 L), followed by cooling to 0.degree. C., and DIBAL
(1.0 M toluene, 2.05 L) was added dropwise thereto for 1 hour. The
resulting reaction solution was cooled to -70.degree. C., and
compound (6-II) (205 g) dissolved in toluene (1.6 L) was added
dropwise thereto. The resulting reaction solution was stirred for
about 2 hours, and its temperature was slowly raised to -40 to
-20.degree. C., followed by stirring for 4 hours. After the
reaction was completed, an aqueous 2N hydrochloric acid solution
(2.5 L) was added. The organic layer was separated, dried over
sodium sulfate (1 kg), filtered and concentrated. The resulting
residue was subjected to chromatography (eluent: n-hexane:ethyl
acetate=1:5) to give the target compound (155 g, Yield: 76%).
Example 7
Preparation of Bimatoprost
##STR00015##
[0058] Compound (1-I) (155 g) was added to a 70% aqueous solution
of ethylamine (3.0 L), followed by stirring at room temperature for
60 hours. After the reaction was completed, the resulting reaction
solution was concentrated to be its half level under reduced
pressure, neutralized with a 2M aqueous solution of sodium
hydrogensulfate (3.0 L, pH=4.about.5) and extracted with ethyl
acetate (3.0 L). The organic layer was dried over sodium sulfate (1
kg), filtered and concentrated. The resulting residue was subjected
to preparative HPLC (eluent: n-hexane:anhydrous ethanol=90:10),
concentrated, and crystallized with diethyl ether (1.5 L). The
resulting solid was filtered and dried under vacuum to give highly
pure bimatoprost (100 g, Purity: 99.5% or more, Yield: 62%).
Example 8
Preparation of Compound (6-III)
##STR00016##
[0060] Pyridinium p-toluensulfonate (PPTS, 4.3 g) was added to
compound (5-I) (217 g) dissolved in a mixture of acetone (1.2 L)
and water (0.2 L), followed by stirring at room temperature for 12
hours. After the reaction was completed, the resulting reaction
solution was concentrated under vacuum, and ethyl acetate (1.5 L)
and water (1.0 L) were added thereto, followed by stirring. The
organic layer was separated, dried over sodium sulfate (1 kg),
filtered and concentrated. The resulting residue was subjected to
chromatography (eluent: n-hexane:ethyl acetate=1:3) to give the
target compound (128 g, Yield: 90%).
Example 9
Preparation of Latanoprost
##STR00017##
[0062] 2,6-Di-tert-butyl-4-methyl phenol (408 g) was dissolved in
toluene (3.7 L), followed by cooling to 0.degree. C., and DIBAL
(1.0 M toluene, 1484 ml) was added dropwise thereto for 1 hour. The
resulting reaction solution was stirred at the same temperature for
1 hour, cooled to -70.degree. C., and compound (6-III) (128 g)
dissolved in toluene (128 ml) was added dropwise thereto. The
resulting reaction solution was stirred at the same temperature for
about 2 hours, and its temperature was slowly raised to -40 to
-20.degree. C., followed by stirring for 4 hours. After the
reaction was completed, an aqueous 2N hydrochloric acid solution
(1.8 L) was added. The organic layer was separated, dried over
sodium sulfate (1 kg), filtered and concentrated. The resulting
residue was subjected to chromatography (eluent: n-hexane:ethyl
acetate=1:3) to give latanoprost (Purity: 96% or more). The
obtained compound was subjected to preparative HPLC (eluent:
heptane:anhydrous ethanol=94:6) to give highly pure latanoprost (96
g, Purity: 99.8% or more, Yield: 75%).
* * * * *