U.S. patent application number 14/928629 was filed with the patent office on 2016-05-19 for process for the preparation of travoprost.
This patent application is currently assigned to CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GY RA ZRT.. The applicant listed for this patent is CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GY RA ZRT.. Invention is credited to Zoltan BISCHOF, d m BODIS, Gabor HAVASI, Iren HORTOB GYI, Zsuzsanna KARDOS, Tibor KISS, Istvan L SZLOFI.
Application Number | 20160137621 14/928629 |
Document ID | / |
Family ID | 47561661 |
Filed Date | 2016-05-19 |
United States Patent
Application |
20160137621 |
Kind Code |
A1 |
KARDOS; Zsuzsanna ; et
al. |
May 19, 2016 |
PROCESS FOR THE PREPARATION OF TRAVOPROST
Abstract
The crystalline compound of formula (III) ##STR00001## having
the melting point of 129.5-134.5.degree. C. is disclosed.
Inventors: |
KARDOS; Zsuzsanna;
(Budapest, HU) ; KISS; Tibor; (Budapest, HU)
; L SZLOFI; Istvan; (Budapest, HU) ; HORTOB GYI;
Iren; (Budapest, HU) ; BISCHOF; Zoltan;
(Budapest, HU) ; BODIS; d m; (Budapest, HU)
; HAVASI; Gabor; (Budapest, HU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GY RA ZRT. |
Budapest |
|
HU |
|
|
Assignee: |
CHINOIN GYOGYSZER ES VEGYESZETI
TERMEKEK GY RA ZRT.
Budapest
HU
|
Family ID: |
47561661 |
Appl. No.: |
14/928629 |
Filed: |
October 30, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14367317 |
Jun 20, 2014 |
9212125 |
|
|
PCT/HU2012/000132 |
Dec 10, 2012 |
|
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14928629 |
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Current U.S.
Class: |
549/312 |
Current CPC
Class: |
Y02P 20/55 20151101;
C07D 307/937 20130101; C07C 2601/08 20170501; C07C 405/00 20130101;
C07C 67/333 20130101; C07D 307/935 20130101 |
International
Class: |
C07D 307/935 20060101
C07D307/935 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2011 |
HU |
P11 00701 |
Claims
1. The crystalline compound of formula (III) ##STR00028## having
the melting point of 129.5-134.5.degree. C.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of copending application
Ser. No. 14/367,317, filed on Jun. 20, 2014, which was filed as PCT
International Application No. PCT/HU2012/000132 on Dec. 10, 2012,
which claims the benefit under 35 U.S.C. .sctn.119(a) to Patent
Application No. P1100701, filed in Hungary on Dec. 21, 2011, all of
which are hereby expressly incorporated by reference into the
present application.
[0002] The subject of our invention is a novel process for the
preparation of travoprost.
[0003] Travoprost of Formula (I)
##STR00002##
is a known prostaglandin derivative used for the treatment of
glaucoma and high eye pressure (U.S. Pat. No. 5,510,383).
[0004] Processes for the preparation of travoprost are disclosed
for example in EP 2143712, WO 2011/046569, WO 2011/055377.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 illustrates the process according to EP 2143712.
[0006] FIG. 2 is the IR spectrum of the Travopost 1.
intermediate.
[0007] FIG. 3 is the IR spectrum of the Travopost 2.
intermediate.
[0008] FIG. 4 is the IR spectrum of the Travopost 3.
intermediate.
[0009] FIG. 5 is the IR spectrum of the Travopost 4.
intermediate.
[0010] FIG. 6 is the IR spectrum of the Travopost 5.
intermediate.
[0011] FIG. 7 is the IR spectrum of Travopost.
[0012] The process according to EP 2143 712 is shown on FIG. 1.
[0013] Stereoselectivity of the enone.fwdarw.enol reduction is
88.7% (Example 10.).
[0014] According to the process disclosed in WO 2011/046569 the
15-epi impurity is removed by protection of the OH-groups of the
diol with tert-butyl-dimethylsilyl group (TBDMS) and
crystallization of the thus obtained protected diol.
[0015] In the process according to WO 2011/055377 the
enone.fwdarw.enol transformation is carried out with
N,N-diethylaniline-borane complex as reducing agent, in the
presence of Corey catalyst (CBS-oxazaborolidine). The product is
purified by preparative HPLC.
[0016] The overall yield is 7%.
[0017] We aimed to work out a process with higher stereoselectivity
and better yield.
[0018] The subject of our invention is the preparation of
travoprost of formula (I)
##STR00003##
by stereoselective reduction of the compound of formula (II),
##STR00004##
reduction of the lactone group of the resulting compound of formula
(III),
##STR00005##
removal of the p-phenylbenzoyl protecting group of the thus
obtained compound of formula (IV),
##STR00006##
transformation of the resulting triol of formula (V) by Wittig
reaction
##STR00007##
into the acid of formula (VI)
##STR00008##
which is then esterified.
[0019] The starting compound of formula (II) can be prepared for
example by oxidation of the PPB-Corey-lactone of formula (XII)
##STR00009##
into the aldehyde, which is then transformed with the phosphonate
of formula (XIII)
##STR00010##
in HWE reaction, in water free medium, in the presence of solid
potassium hydroxide into the compound of formula (II).
[0020] According to one embodiment of the process based on the
invention, the PPB-Corey-lactone is oxidized under Pfitzner-Moffatt
reaction conditions into the aldehyde (Pfitzner, K. E., Moffatt J.
G.; J. Am. Chem. Soc. 1963, 85, 3027), then the lower chain is
built up with the help of Horner-Wadsworth-Emmons (HWE) reaction
(Wadsworth, W.; Org. React., 1977, 25, 73)--by use of the
appropriate phosphonate--under water-free conditions, in the
presence of solid potassium hydroxide. For the deprotonation of the
phosphonate--instead of using the widely described sodium hydride,
potassium tert-butylate, lithium carbonate, DBU, lithium- or
magnesium halogenides, triethylamine, potassium hexamethyl
disilazide (KHMDS) or crown ether bases--we applied solid potassium
hydroxide which is economical and can be safely used in industrial
scale.
[0021] The HWE reaction is carried out in an aprotic organic
solvent in a temperature range of 40-(-50).degree. C., preferably
at (-10).degree. C., by using as solvent an aromatic hydrocarbon,
such as toluene or an ether, like tetrahydrofuran,
methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane,
tert-butyl methyl ether, diisopropyl ether, diethyl ether or their
mixtures. According to another embodiment of the invention, the
selective reduction of the compound of formula (II) is accomplished
with a borane-type reducing agent.
[0022] As the borane-type reducing agent borane-dimethyl sulfide,
(-)-B-chlorodiisopinocampheylborane (DIP-Cl), catecholborane,
especially catecholborane may be applied. According to a further
embodiment of the process the reduction of the compound of formula
(II) is carried out in the presence of a chiral catalyst. As chiral
catalyst CBS-oxazaborolidine can be used. The reaction is carried
out in the presence of an organic solvent, at a temperature between
(10.degree. C.) and (-80.degree. C.), preferably between
(-10.degree. C.) and (-20.degree. C.). As for solvent toluene,
hexane, heptane, pentane, tetrahydrofuran, methyltetrahydrofuran,
cyclopentyl methyl ether, dimethoxyethane, tert-butyl methyl ether,
diisopropyl ether, diethyl ether or their mixtures may be applied,
among others toluene-tetrahydrofuran mixtures are used.
[0023] The resulting compound of formula (III) is purified by
crystallization, while the amount of the undesired isomer is
lowered in a significant manner. The crystalline form of the
compound of formula (III) has not been known before, it is a novel
form. Crystallization is carried out in polar or apolar solvents or
in the mixture of them.
[0024] In an embodiment of the process according to the invention
the crystallization is performed between (-20)-70.degree. C., in
such a way that the material is dissolved in alcohol at reflux
temperature and crystallized by cooling gradually. The crystals are
then filtered off, washed and dried.
[0025] Reduction of the compound of formula (III) may be carried
out with diisobutyl-aluminum hydride (DIBAL-H). As for solvent,
inert aprotic solvents such as THF, toluene, hexane, and heptane
may be applied. The reaction is performed at a temperature between
(-80.degree. C.) and (-50.degree. C.), especially between
(-80.degree. C.) and (-70.degree. C.).
[0026] The product of the DIBAL-H reduction, the intermediate of
formula (IV), is a novel compound.
[0027] The PPB-protecting group may be removed in a known way by
methanolysis, under basic conditions, especially in the presence of
potassium carbonate.
[0028] In a further embodiment of the process, the resulting
intermediate of formula (V) is purified by crystallization, while
the amount of the undesired isomer is decreased under a strickt
limit value. The crystalline form of the compound of formula (V)
has not been described before, it is a novel form. Crystallization
is carried out in the mixture of polar and apolar solvents. As for
the mixture of polar and apolar solvents, an ethyl acetate-hexane
mixture may be used. Transformation of the compound of formula (V)
into the compound of formula (VI) is accomplished by Wittig
reaction, while esterification of the compound of formula (VI) is
carried out with isopropyl iodide.
[0029] In the esterification reaction cyclic tertiary amides, such
as N-methylpyrrolidone and/or 1,3-dimethylimidazolidinone are used
as solvents. The esterification is performed at a temperature
between 20-90.degree. C., especially between 40-50.degree. C.
[0030] A further subject of the invention is the novel compound of
formula (IV)
##STR00011##
and its use for the preparation of Travoprost.
[0031] Furthermore, the subject of the invention is the crystalline
compound of formula (III),
##STR00012##
having the melting point of 129.5-134.5.degree. C., and its use for
the preparation of Travoprost.
[0032] Furthermore, the subject of the invention is the crystalline
compound of formula (V),
##STR00013##
having the melting point of 85.4-86.6.degree. C., and its use for
the preparation of Travoprost.
[0033] One embodiment of the full synthesis of Travoprost according
to the invention is demonstrated on Scheme 1 below:
##STR00014## ##STR00015##
[0034] In one embodiment of the invention, which starts from the
PPB-Corey-lactone, the lower chain is constructed with the help of
the appropriate phosphonate, by Horner-Wadsworth-Emmons reaction.
For the deprotonation of the phosphonate the inexpensive and in
industrial scale safely applicable solid potassium hydroxide is
used. Reduction of the resulting Travoprost 1. intermediate
(enone--compound of Formula (II)) is carried out in the presence of
a 2-methyl-CBS-oxazaborolidine catalyst, with a borane-type
reducing agent, like catecholborane, resulting in a
stereoselectivity of 90%. The thus obtained Travoprost 2.
intermediate (enol--compound of Formula (III)) is purified by
crystallization and reduced with diisobutylaluminum hydride
(DIBAL-H). From the resulting Travoprost 3. intermediate
(PPB-triol--compound of Formula (IV)) the PPB-protecting group is
removed and the thus obtained Travoprost 4. intermediate
(triol--compound of Formula (V)) is purified by crystallization.
Travoprost 5. intermediate (acid--compound of Formula VI) is
prepared by Wittig reaction. Finally, the esterification is carried
out with isopropyl iodide in DMI (1,3-dimethylimidazolidin-2-one)
solvent to obtain the ester (Travoprost--Formula (I)).
[0035] Advantages of the process introduced by the invention:
[0036] In the HWE reaction, to prepare the starting compound of
formula (II), the deprotonation of the phosphonate is carried out
with the inexpensive and in industrial scale safely applicable
solid potassium hydroxide--instead of the expensive and flammable
sodium hydride which is commonly and widely used in the present
practice. [0037] The use of CBS-oxazaborolidine and catecholborane
for the reduction of the 15-oxo group in the synthesis of
travoprost is a new solution, not applied before, by which a
diastereomeric excess even higher than 90-92% may be reached. In
the method described in EP 2 143712 the selectivity is de(S)=88.7%,
using DIP-Cl. In the process disclosed in WO 2011/055377 A1, beside
the CBS catalyst N,N-diethylaniline-borane complex is applied, but
the extent of stereoselectivity is not given. [0038] The
purification strategy is fully novel, since removal of the
15-epi-impurity is accomplished by crystallization, without
chromatography, in a high yield, contrary to the MPLC (medium
pressure chromatography purification method) (WO 2011/046569 A1) or
preparative HPLC (WO 2011/055377 A1) methods known in the
literature. [0039] The crystalline form of the compound of formula
(III) and that of the compound of formula (V) have not been
described in the literature before. In the present process the
crystalline form is also utilized for the purification of the
intermediates and removal of the undesired isomer. [0040] In the
esterification step, as a novel solvent,
1,3-dimethylimidazolidinone (DMI) is used, which is not strongly
toxic, in contrast to the generally used dimethylformamide (EP 2
143 712 A1, WO 2011/046569 A1). DMI is a solvent used in the beauty
industry. As a further advantage, the formyl-impurities which
generate from the widely used dimethylformamide solvent, are not
formed from DMI. The esterification reaction can be carried out
with very high conversion, without forming new impurities
(.about.100%). [0041] The overall yield of the new process is very
high, 16%, which is more than double of the yield described in WO
2011/055377 A1 (7%). [0042] Further details of the invention are
included, but not limited to the examples below.
EXAMPLES
1. Construction of the Lower Chain (Oxidation and HWE Reaction)
Preparation of the [1,1'-Biphenyl]-4-carboxylic acid, (3
aR,4R,5R,6aS)-hexahydro-2-oxo-4-[(1E)-3-oxo-4-[3-(trifluoromethyl)phenoxy-
]-1-buten-1-yl]-2H-cyclopenta[b]furan-5-yl ester
[0043] /Compound of Formula (II)/
##STR00016##
1069 g of PPB-Corey-lactone is suspended in an inert atmosphere in
11.1 L of water-free toluene. To this suspension are added 1.4 L of
diisopropylcarbodiimide and then 0.855 L of dimethyl sulfoxide in
phosphoric acid. The reaction mixture is heated to 50.degree. C.
and a further 0.34 L of dimethyl sulfoxide in phosphoric acid is
added in portions. After the accomplishment of the oxidation
reaction, the mixture is cooled to -10.degree. C. and while that
temperature is maintained, 316 g of potassium hydroxide followed by
1.45 kg of Travoprost phosphonate in toluene solution are added.
When the HWE reaction has completed, the reaction mixture is poured
onto 1 M hydrochloric acid solution and the mixture is stirred. The
precipitated crystals are filtered off and washed. The phases of
the filtrate are separated, the organic phase is washed with 1M
sodium hydrogen carbonate solution and then with diluted
hydrochloric acid solution. The organic phase is evaporated and
purified by chromatography on a silica gel column
(eluent:toluene-ethyl acetate mixture). The main fraction is
evaporated and crystallized from ethyl acetate-hexane mixture.
[0044] Yield: 915 g, 55%.
[0045] Melting point: 112.5-114.5.degree. C.
[0046] IR spectrum of Travoprost 1. intermediate is shown on FIG.
2.
[0047] Travoprost 1. Intermediate .sup.1H, .sup.13C and .sup.19F
NMR Data:
##STR00017##
[0048] Travoprost 1. Intermediate (Enone--Formula (II)):
TABLE-US-00001 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6
176.56 -- -- 7 34.46 .beta.: 2.96* 1 m (dd) J.sub.gem = 17.3;
J.sub.7.beta.,8 = 10.2 .alpha.: 2.55 1 d 8 42.17 3.00* 1 m (dddd) 9
83.32 5.13 1 td J.sub.8,9 = J.sub.9,10.beta. = 6.4;
J.sub.9,10.alpha. = 1.3 10 37.50 .beta.: 2.63 1 dt J.sub.gem =
15.2; J.sub.10.beta.,11 = 6.4; .alpha.: 2.14 1 dd
J.sub.10.alpha.,11 = 3.6 11 78.95 5.35 1 dt J.sub.11,12 = 5.6 12
53.66 3.10 1 m (ddd) J.sub.8,12 = 5.0 13 146.19 6.99 1 dd
J.sub.13,14 = 16.0; J.sub.12,13 = 8.1 14 127.24 6.44 1 d 15 194.08
-- -- -- 16 71.12 5.17 2 s 17 158.14 -- -- -- 18 111.16 (q) 7.22**
1 broad .sup.3J.sub.C-18,F = 3.8; J.sub.18,20 = 1.5; J.sub.18,22 =
2.5 19 130.24 (q) -- -- -- .sup.2J.sub.C-19,F = 31.7 20 117.50 (q)
7.285 1 m (d) .sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 7.8;
J.sub.20,22 = 0.8; 21 130.63 7.495*** 1 m (dd) J.sub.21,22 = 8.2 22
118.75 7.20** 1 m (dd) 23 123.95 (q) -- -- -- .sup.1J.sub.C-23,F =
272.5 23-F -61.10 (s, 3) -- -- -- 24 164.94 -- -- -- 25 128.16 --
-- -- 26, 26' 129.95 8.015 2 m J.sub.26,27 = 8.5; 27, 27' 126.87
7.81 2 m 28 144.93 -- -- -- 29 138.77 -- -- -- 30, 30' 127.01 7.74
2 m (dd) J.sub.30,31 = 7.4 31, 31' 129.10 7.51*** 2 m (t)
J.sub.31,32 = 7.4 32 128.46 7.43 1 m (tt) J.sub.30,32~1.6 *, **,
***Overlapping .sup.1H NMR signals
2. 15-Oxo-Reduction (Stereoselective Reduction)
Preparation of [1,1'-Biphenyl]-4-carboxylic acid,
(3aR,4R,5R,6aS)-hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phen-
oxy]-1-buten-1-yl]-2-oxo-2H-cyclopenta[b]furan-5-yl ester
[0049] /Compound of Formula (III)/
##STR00018##
[0050] 279 ml of catecholborane is dissolved in 4.6 L of
tetrahydrofuran (THF) and the 1M toluene solution of 549 ml of
R-(+)-2-methyl-CBS-oxazaborolidine is added to it. The mixture is
cooled to -10.degree. C. and while that temperature is maintained,
the solution of 915 g of Travoprost 1. intermediate
(enone--compound of Formula (II)) in 6.9 L of THF is added. When
the reaction has completed, the mixture is decomposed by stirring
with 13 L of 1 M NaHSO.sub.4 solution. Ethyl acetate is then added
and the phases are separated. The organic phase is washed with NaOH
solution and then with hydrochloric acid solution. The organic
phase is dried over sodium sulfate, filtered, evaporated and
crystallized first from hexane:acetone mixture, then from methanol
for removing the undesired isomer de(S)92%.fwdarw.de(S)98%. (de
means: diastereomeric excess)
[0051] Yield: 701 g, 55% de(S): 98%
[0052] M.p.: 129.5-134.5.degree. C.
[0053] IR spectrum of Travoprost 2. intermediate is shown on FIG.
3.
[0054] Travoprost 2. Intermediate .sup.1H, .sup.13C and .sup.19F
NMR Data:
##STR00019##
TABLE-US-00002 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6
176.76 -- -- -- 7 34.53 .beta.: 2.93 1 dd J.sub.gem = 17.8;
J.sub.7.beta.,8 = 10.0 .alpha.: 2.46 1 dd J.sub.7.alpha.,8 = 0.9 8
42.14 2.85* 1 m (dddd) 9 83.28 5.09 1 td J.sub.8,9 =
J.sub.9,10.beta. = 6.5; J.sub.9,10.alpha. = 1.4 10 37.20 .beta.:
2.55 1 dt J.sub.gem = 15.2; J.sub.10.beta.,11 = 6.4; .alpha.: 2.05
1 m (dd) J.sub.10.alpha.,11 = 4.6 11 79.58 5.20 1 m (ddd/dt)
J.sub.11,12~5.5 12 53.49 2.83* 1 m (ddd) 13 129.87.sup.$ 5.76** 1 m
14 132.18 5.76** 1 m 15 68.83 4.34 1 m (broad) 15-OH 5.26 1 d
J.sub.15, OH = 4.9 16 72.18 a: 3.95 1 dd J.sub.gem = 9.8;
J.sub.15,16a = 4.6; b: 3.90 1 dd J.sub.15,16b = 6.7 17 158.88 -- --
-- 18 111.08 (q) 7.195*** 1 m .sup.3J.sub.C-18,F = 3.7 19 130.25
(q) -- -- -- .sup.2J.sub.C-19,F = 31.5 20 117.04 (q) 7.25 1 d
.sup.3J.sub.C-20,F = 3.7; J.sub.20,21 = 7.7; J.sub.18,20 = 1.4;
J.sub.20,22 = 1.0 21 130.63 7.47.sup.# 1 m (t/dd) J.sub.21,22 = 8.2
22 118.80 7.20*** 1 m J.sub.18,22 = 2.5; 23 123.98 (q) -- -- --
.sup.1J.sub.C-23,F = 272.4 23-F -61.16 (s, 3) -- -- -- 24 165.02 --
-- -- 25 128.33 -- -- -- 26, 26' 129.87.sup.$ 7.99 2 d J.sub.26,27
= 8.4 27, 27' 126.80 7.77 2 d 28 144.81 -- -- -- 29 138.77 -- -- --
30, 30' 126.97 7.72 2 d J.sub.30,31 = 7.4 31, 31' 129.07 7.50.sup.#
2 m (t) J.sub.31,32 = 7.4 32 128.42 7.43.sup.# 1 m (tt) *, **, ***,
.sup.#, .sup.##Overlapping .sup.1H NMR signals. .sup.$Overlapping
.sup.13C NMR signals.
3. Lactone Reduction (Preparation of the Lactol)
Preparation of [1,1'-Biphenyl]-4-carboxylic acid, (3
aR,4R,5R,6aS)-hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenox-
y]-1-buten-1-yl]-2-hydroxy-cyclopenta[b]furan-5-yl ester
[0055] /Compound of Formula (IV)/
##STR00020##
[0056] A multi-neck flask is charged under nitrogen atmosphere with
701 g of enol which is then dissolved in 6.8 L of room temperature
THF. The clear solution is cooled to -75.degree. C. and in
approximately 30 minutes the pre-cooled (-75.degree. C.) 1 M hexane
solution of 2921 ml diisobutylaluminum hydride (DIBAL-H) is added
to it. The reaction mixture is stirred at -75.degree. C. until the
reaction is completed. After reaching the suitable conversion, the
reaction mixture is poured onto the mixture of NaHSO.sub.4 solution
and ethyl acetate. The phases are separated, the aqueous phase is
extracted with ethyl acetate, the united organic phase is washed
with NaHCO.sub.3 solution and with diluted hydrochloric acid
solution, and then evaporated while adding triethylamine (TEA) to
it. 639.5 g oil is obtained.
[0057] Yield: 639.5 g, 91%
[0058] IR spectrum of Travoprost 3. intermediate is shown on FIG.
4.
[0059] Travoprost 3. Intermediate .sup.1H, .sup.13C and .sup.19F
NMR Data:
##STR00021##
[0060] Travoprost 3. Intermediate, Diastereomer A
TABLE-US-00003 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6
98.78 5.53 1 td J.sub.6,OH = 4.6; J.sub.6,7 = 2.2 and 4.6 6-OH 6.02
1 d 7 39.31.sup.$ a: 1.93* 1 m b: 1.89* 1 m 8 45.28 2.565** 1 m 9
79.43 4.565 1 td J.sub.8,9 = 6.2; J.sub.9,10 = 2.7 and 6.2 10 37.21
.beta.: 2.51 1 m J.sub.gem~14.0 .alpha.: 1.74*** 1 m (ddd)
J.sub.10.alpha.,11 = 6.9 11 79.72 5.08 1 m (q/dt) J.sub.10.beta.,11
= J.sub.11,12 = 6.9 12 53.23 2.575** 1 m 13 130.60 5.75.sup.+ 1 dd
J.sub.13,14 = 15.6; J.sub.12,13 = 6.5 14 131.71 5.70.sup.+ 1 dd
J.sub.14,15 = 4.5 15 68.79 4.32.sup.++ 1 m (dddd) 15-OH
5.23.sup.+++ 1 m (d) J.sub.15,OH = 5.0 16 72.23.sup.$$ a:
3.91.sup.# 1 m (dd) J.sub.gem = 9.7; J.sub.15,16a = 4.8; b:
3.87.sup.# 1 m (dd) J.sub.15,16b = 6.7 17 158.88.sup.$$ -- -- -- 18
111.09 (q) 7.16.sup.## 1 m .sup.3J.sub.C-18,F = 3.6;
J.sub.18,20~J.sub.18,22~1.3 19 130.24.sup.$$ (q) -- -- --
.sup.2J.sub.C-19,F = 31.7 20 117.01.sup.$$ (q) 7.22.sup.### 1 m
.sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 7.8 21 130.56
7.44.sup.& 1 m (t/dd) J.sub.21,22 = 7.8 22 118.73 7.15.sup.## 1
m 23 123.97.sup.$$ (q) -- -- -- .sup.1J.sub.C-23,F = 272.4 23-F
-61.19 (s, 3) -- -- -- 24 165.16 -- -- -- 25 128.61 -- -- -- 26,
26' 129.75.sup.$$ 7.985.sup.&& 2 d J.sub.26,27 = 8.4 27,
27' 126.90.sup.$$ 7.77 2 d 28 144.71.sup.$$ -- -- -- 29
138.84.sup.$$ -- -- -- 30, 30' 126.96.sup.$$
7.70.sup.&&& 2 m (d) J.sub.30,31 = 7.5 31, 31'
129.07.sup.$$ 7.50 2 m (t/dd) J.sub.31,32 = 7.4 32 128.40.sup.$$
7.43.sup.& 1 m (tt) *, **, ***, .sup.+, .sup.++, .sup.+++,
.sup.#, .sup.##, .sup.###, .sup.&, .sup.&&,
.sup.&&&, Overlapping .sup.1H NMR signals.
.sup.$Overlapping .sup.13C NMR signals with the DMSO signal.
.sup.$$Overlapping .sup.13C NMR signals.
[0061] Travoprost 3. Intermediate, Diastereomer B
TABLE-US-00004 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6
99.70 5.45 1 m (td/ddd) J.sub.6,7 = 0.9 and 4.5 6-OH 6.25 1 d
J.sub.6,OH = 3.4 7 37.51 .beta.: 1.99 1 m J.sub.7,8.beta. = 5.7
.alpha.: 1.73*** 1 m J.sub.gem~11.8; J.sub.6,7.alpha. = 1.9 8 44.64
2.41 1 m (q/ddd) J.sub.8,12 = 10.1 9 80.04 4.46 1 td J.sub.8,9 =
J.sub.9,10.beta. = 7.3; J.sub.9,10.alpha. = 5.2 10 39.45.sup.$
.beta.: 2.65 1 dt J.sub.gem = 13.0; J.sub.10.beta.,11 = 7.3
.alpha.: 1.90* 1 m 11 78.11 5.00 1 td J.sub.10.alpha.,11 =
J.sub.11,12 = 9.8 12 52.34 3.10 1 td J.sub.12,13 = 7.1 13 130.74 14
131.85 15 68.68 15-OH 5.21.sup.+++ 1 m (d) J.sub.15,OH = 5.1 16
72.25.sup.$$ a: 3.88.sup.# 1 m J.sub.gem = 9.7 b: 3.84.sup.# 1 m
(dd) J.sub.15,16b = 6.6 17 158.86.sup.$$ -- -- -- 19 130.22.sup.$$
(q) -- -- -- .sup.2J.sub.C-19,F = 31.7 20 116.97.sup.$$ (q)
7.205.sup.### 1 m .sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 7.8 21
7.41.sup.& 1 m (dd) J.sub.21,22 = 8.1 22 118.64 7.11.sup.## 1 m
(dd) 2.3; 0.8 23 123.95.sup.$$ (q) -- -- -- .sup.1J.sub.C-23,F =
272.4 23-F -61.21 (s, 3.sup.%) -- -- 24 165.28 -- -- -- 25 128.57
-- -- -- 26, 26' 129.76.sup.$$ 7.995.sup.&& 2 d J.sub.26,27
= 8.4 27, 27' 126.85.sup.$$ 7.73 2 d 28 144.68.sup.$$ -- -- -- 30,
30' 126.94.sup.$$ 7.68.sup.&&& 2 m (d) J.sub.30,31 =
7.5 31, 31' 129.065.sup.$$ *, ***, .sup.+++, .sup.#, .sup.##:
.sup.###, .sup.&, .sup.&&,
.sup.&&&Overlapping .sup.1H NMR signals.
.sup.$Overlapping .sup.13C NMR signals with the signal of DMSO.
Overlapping .sup.1H NMR signals with the signal of ethyl acetate.
.sup.$$Overlapping .sup.13C NMR signals. .sup.%The presence of the
3 fluoro atoms is shown by the .sup.19F and .sup.13C NMR
spectra.
4. Removal of the Protecting Group (Preparation of the Triol)
4a.
Preparation of 2H-cyclopenta[b]furan-2,5-diol,
hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-y-
l]-(3 aR,4R,5R,6aS)-
[0062] /Compound of Formula (V)/
##STR00022##
[0063] 639.5 g of PPB-triol is dissolved in 6.4 L of methanol and
the solution is heated to 40.degree. C. 95 g of K.sub.2CO.sub.3 is
added and the mixture is stirred at 40.degree. C. until the
reaction is completed. After reaching the suitable conversion, the
reaction mixture is cooled to 2.degree. C. and phosphoric acid
solution is added in portions. The precipitated PPB-methyl ester
crystals are filtered off and washed. The filtrate is concentrated,
water and ethyl acetate are added and the phases are separated. The
aqueous phase is extracted with ethyl acetate, dried over
Na.sub.2SO.sub.4 and the solution is evaporated. The crude oil is
crystallized from ethyl acetate:hexane mixture. The precipitated
crystals are filtered off, washed with hexane:ethyl acetate mixture
and dried.
[0064] Yield: 367 g, 85%
[0065] Melting point: 85.4-86.6.degree. C.
4b.
Recrystallyzation of 2H-cyclopenta[b]furan-2,5-diol,
hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-y-
l]-(3aR,4R,5R,6aS)-
[0066] /Compound of Formula (V)--the Triol/
[0067] The precipitated crystals are solved in 10 folds
ethyl-acetate, thereafter 10 folds n-hexane is added and the
solution is mixed at room temperature. To the crystal-suspension
obtained 20 folds n-hexane is added and mixed at room temperature.
The precipitated crystals are filtered, washed with a mixture of
hexane:ethyl-acetate and dried. With repetition of the above
process at any time the amount of the undesired isomer may be
lowered to any amount, also decreasing of the amount of the
undesired isomer under the disregard limit (<0.05%) is
possible.
[0068] Yield: 52-85% (depending of the number of
recrystallizations)
[0069] IR spectrum of Travoprost 4. intermediate is shown on FIG.
5.
[0070] Travoprost 4. Intermediate .sup.1H, .sup.13C and .sup.19F
NMR Data:
##STR00023##
[0071] Travoprost 4. Intermediate, Diastereomer A .sup.1H, .sup.13C
and .sup.19F NMR Data:
TABLE-US-00005 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6
98.73 5.42 1 td J.sub.6,7~4.6 and 2.6 6-OH 5.90 1 d J.sub.6,OH =
4.6 7 39.04.sup.$ 1.75 2 m 8 44.65 2.27** 1 m 9 78.29 4.345*** 1 td
J.sub.8,9 = J.sub.9,10.beta. = 7.1; J.sub.9,10.alpha. = 4.3 10
40.58 .beta.: 2.24** 1 m J.sub.gem = 14.0; J.sub.10.alpha.,11 = 9.1
.alpha.: 1.44 1 m (ddd) 11 76.60 3.67 1 m (dddd) J.sub.10.beta.,11
= 7.2; J.sub.11,12 = 9.2 11-OH 4.80 1 d J.sub.6,OH = 5.9 12 55.97
1.95.sup.+ 1 m (td) J.sub.8,12 = 9.2; J.sub.12,13 = 7.4 13 132.44
5.69 1 dd J.sub.13,14 = 15.6 14 130.30 5.55 1 dd J.sub.14,15 = 5.6
15 69.24 4.32*** 1 m 15-OH 5.16.sup.++ 1 d J.sub.15,OH = 4.9 16
72.48.sup.$$ a: 3.97.sup.+++ 1 m (dd) J.sub.gem = 9.9; J.sub.15,16a
= 4.4; b: 3.92.sup.# 1 m (dd) J.sub.15,16b = 7.0 17 158.99.sup.$$
-- -- -- 18 111.17 (q) 7.22 1 m (dd) .sup.3J.sub.C-18,F = 3.7;
J.sub.18,20 = 1.6; J.sub.18,22 = 3.6 19 130.28 (q) -- -- --
.sup.2J.sub.C-19,F = 31.7 20 117.04 (q) 7.27.sup.## 1 m (dd)
.sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 8.0 21 130.70 7.51 1 m (t)
J.sub.21,22 = 8.0 22 118.93 7.25.sup.## 1 m (dd) J.sub.20,22 = 1.0
23 124.03 (q) -- -- -- .sup.1J.sub.C-23,F = 272.5 23-F -61.14 (s,
3) -- -- -- *, **, ***, .sup.+, .sup.++, .sup.+++, .sup.#,
.sup.##Overlapping .sup.1H NMR signals. .sup.$Overlapping .sup.13C
NMR signals with the signal of DMSO. .sup.$$Overlapping .sup.13C
NMR signal.
[0072] Travoprost 4. Intermediate, Diastereomer B .sup.1H, .sup.13C
and .sup.19F NMR Data:
TABLE-US-00006 Coupling constant (Hz) Numbering .sup.13C (ppm)
.sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 6 99.55
5.36 1 m (t/ddd) J.sub.6,7.beta. = 5.1 6-OH 6.10 1 d J.sub.6,OH =
3.8 7 37.86 .beta.: 1.92.sup.+ 1 m J.sub.7,8.beta. = 5.7 .alpha.:
1.61 1 m J.sub.gem = 12.9; J.sub.6,7.alpha.~1.5 8 44.85 2.18** 1 m
(dt/dddd) J.sub.7.alpha.,8~1.5; J.sub.8,12 = 9.9 9 80.07 4.28*** 1
td J.sub.8,9 = J.sub.9,10.beta. = 7.8; J.sub.9,10.alpha. = 5.7 10
42.88 .beta.: 2.26** 1 m J.sub.gem = 12.7; J.sub.10.alpha.,11 = 9.9
.alpha.: 1.72* 1 m (ddd) 11 76.02 3.59 1 m (dddd)
J.sub.10.alpha.,11 = 6.5; J.sub.11,12 = 9.9 11-OH 4.75 1 d
J.sub.6,OH = 5.9 12 55.03 2.52.sup.### 1 m (td) J.sub.12,13~7.3, 13
133.10 14 130.08 15 69.32 15-OH 5.15.sup.++ 1 m (d) J.sub.15,OH =
4.9 16 72.53.sup.$$ a: 3.98.sup.# 1 m (dd) J.sub.gem = 9.9;
J.sub.15,16a = 4.4 b: 3.92.sup.# 1 m (dd) J.sub.15,16b = 6.9 17
159.01.sup.$$ -- -- -- *, ***, .sup.+++, .sup.#, .sup.##Overlapping
.sup.1H NMR signals. .sup.###Overlapping .sup.1H NMR signals with
the signal of DMSO. .sup.$$Overlapping .sup.13C NMR signals.
5. Construction of the Upper Chain (Preparation of Travoprost
Acid)
Preparation of 5-heptanoic acid,
7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl-
)phenoxy]-1-buten-1-yl]cyclopentyl]-(5Z)-
[0073] /Compound of formula (VI)/
##STR00024##
[0074] Under nitrogen atmosphere 1509 g of
4-carboxybutyl-phosphonium bromide (KBFBr) is dissolved in 12.8 L
of THF, the solution is cooled to 0.degree. C., and by maintaining
that temperature, 1.12 kg of potassium tert-butylate is added to it
in portions. After 15 minutes of stirring the reaction mixture is
cooled to (-10).degree. C., then 367 g of triol dissolved in 2.24 L
of THF is added and the mixture is stirred at (-10).degree. C. When
the reaction has completed, the reaction mixture is decomposed with
water and toluene is added. The aqueous phase is extracted with
dichloromethane (DKM) and acidified with a solution of NaHSO.sub.4.
Ethyl acetate is then added, the phases are separated and the
aqueous phase is extracted with ethyl acetate. The united organic
phase is washed with a diluted sodium chloride solution, dried over
Na.sub.2SO.sub.4, the drying material is filtered off, the filtrate
is washed and the filtrate solution is evaporated. The residue is
crystallized from acetone:diisopropyl ether mixture. The crystals
are filtered off, washed with diisopropyl ether:acetone mixture.
The mother liquor is evaporated.
[0075] Yield: 463 g, 103%
[0076] IR spectrum of Travoprost 5. intermediate is shown on FIG.
6.
[0077] Travoprost 5. intermediate .sup.1H, .sup.13C and .sup.19F
NMR data:
##STR00025##
TABLE-US-00007 Coupling constant .sup.13C/.sup.19F (Hz) Numbering
(ppm) .sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 1
174.37 -- -- -- 1-COOH 11.95 1 broad (s) 2 33.09 2.13* 2 t
J.sub.2,3 = 7.4 3 24.46 1.49** 2 m (tt) J.sub.3,4 = 7.4 4 26.06
1.96*** 2 m 5 128.56 5.23 1 dt J.sub.5,6 = 10.7; J.sub.4,5 = 7.2 6
129.73 5.43 1 dt J.sub.6,7 = 7.4 7 24.78 b: 2.10* 1 m a: 1.96*** 1
m 8 48.78 1.32 1 m (dddd/tt) 11.1; 10.0; 5.0; 5.0 9 69.58
3.90.sup.+ 1 m 9-OH 4.36.sup.++ 1 broad (s) 10 43.96 b: 2.20* 1 ddd
J.sub.gem = 14.1; J.sub.10b,11 = 8.4; a: 1.44** 1 ddd J.sub.9,10b =
5.8; J.sub.10a,11 = 5.6; J.sub.9,10a = 2.3; 11 75.64 3.69 1 m 11-OH
4.53 1 broad (s) 12 54.30 2.18* 1 m (td) 13 133.97 5.57 1 dd
J.sub.13,14 = 15.5; J.sub.12,13 = 8.0 14 131.01 5.51 1 dd
J.sub.14,15 = 5.7 15 69.51 4.32.sup.++ 1 q (ddd) 5.6 15-OH 5.125 1
broad (s) 16 72.55 b: 3.96.sup.+ 1 dd J.sub.gem = 9.9; J.sub.15,16b
= 4.9 a: 3.93.sup.+ 1 dd J.sub.15,16a = 6.6 17 158.97 -- -- -- 18
111.13 (q) 7.20.sup.+ 1 m (t/dd) .sup.3J.sub.C-18,F = 3.7;
J.sub.18,20 = 1.5; J.sub.18,22 = 2.5 19 130.29 (q) -- -- --
.sup.2J.sub.C-19,F = 31.7 20 117.01 (q) 7.26.sup.+++ 1 m (ddd)
.sup.3J.sub.C-20,F = 3.8; J.sub.20,21 = 7.8; J.sub.20,22 = 0.7 21
130.68 7.50 1 t (dd) J.sub.21,22 = 8.2 22 118.75 7.24.sup.+++ 1 m
(ddd) 23 124.01 (q) -- -- -- .sup.1J.sub.C-23,F = 272.4 23-F -61.19
(s, 3) -- -- -- *, **, ***, .sup.+, .sup.++, .sup.+++Overapping
.sup.1H NMR signals.
6. Preparation of Travoprost /Compound of Formula (I)/
##STR00026##
[0079] 463 g of Travoprost acid is dissolved in 2.3 L of
1,3-dimethylimidazolidinone (DMI), and 420 g of K.sub.2CO.sub.3 and
300 ml of isopropyl iodide are added. The reaction mixture is
stirred at 45.degree. C. After the completion of the reaction
NaHSO.sub.4 solution, water, hexane and ethyl acetate are added.
The mixture is shaken, then the phases are separated and the lower,
aqueous phase is extracted with hexane:ethyl acetate mixture. The
united organic phase is washed with water, dried over
Na.sub.2SO.sub.4, the drying material is filtered off and the
solution is evaporated. The product is purified by chromatography
on silica gel, using diisopropyl ether, acetone, dichloromethane,
isopropanol mixture as eluent.
[0080] Yield: 338.7 g, 67%
[0081] IR spectrum of Travoprost is shown on FIG. 7.
[0082] Travoprost .sup.1H, .sup.13C and .sup.19F NMR data:
##STR00027##
TABLE-US-00008 Coupling constant (Hz) Numbering .sup.13C (ppm)
.sup.1H (ppm) Number of .sup.1H Multiplicity (+/-0.2 Hz) 1 172.23
-- -- -- 2 33.19 2.16* 2 t J.sub.2,3 = 7.3 3 24.42 1.49** 2 tt
J.sub.3,4 = 7.3 4 25.93 1.96*** 2 m (q) J.sub.4,5 = 7.3 5 128.36
5.23 1 dt J.sub.5,6 = 10.7 6 129.85 5.44 1 dt J.sub.6,7 = 7.4 7
24.75 b: 2.09 1 m (dt) a: 1.96*** 1 m 8 48.76 1.31 1 m (dddd/tt)
11.2; 10.0; 4.8; 4.8 9 69.54.sup.$ 3.90 1 m (dddd) 2.0; 5.3; 5.3,
5.3 9-OH 4.36 1 d J.sub.9,OH = 4.9 10 43.96 b: 2.20* 1 m (ddd)
J.sub.gem = 14.1; J.sub.10b,11 = 8.7; a: 1.44** 1 ddd J.sub.9,10b =
5.9; J.sub.10a,11 = 5.7; J.sub.9,10a = 2.3; 11 75.63 3.69 1 m
(dddd/tt) 7.9; 7.9; 5.9; 5.9 11-OH 4.54 1 d J.sub.11,OH = 5.8 12
54.30 2.175* 1 m 13 134.01 5.57 1 dd J.sub.13,14 = 15.5;
J.sub.12,13 = 8.0 14 131.03 5.51 1 dd J.sub.14,15 = 6.0 15
69.54.sup.$ 4.315 1 qui (tt) 5.5 15-OH 5.12 1 d J.sub.15,OH = 4.8
16 72.55 a: 3.94 1 m b: 3.95 1 m 17 158.96 -- -- -- 18 111.07 (q)
7.20 1 m .sup.3J.sub.C-18,F = 3.7; J.sub.18,20 = J.sub.18,22 = 2.0
19 130.28 (q) -- -- -- .sup.2J.sub.C-19,F = 31.8 20 117.02 (q)
7.27.sup.+ 1 t .sup.3J.sub.C-20,F = 3.9; J.sub.20,21 = 8.0;
J.sub.20,22 = 0.7 21 130.67 7.51 1 t J.sub.21,22 = 8.0; 22 118.77
7.24.sup.+ 1 dd 23 124.01 (q) -- -- -- .sup.1J.sub.C-23,F = 272.2
23-F -61.28 (s, 3) -- -- -- 24 66.80 4.84 1 sep J.sub.24,25 = 6.3
25; 26 21.55 1.13 6 d .sup.$: Overlapping .sup.13C NMR signals. *,
**, ***, .sup.+Overapping .sup.1H NMR signals.
* * * * *