An improved synthesis of latanoprost involving effective control on 15(S) diastereomer

Article abstract of DOI:10.1080/00397911.2019.1622018

An improved process for the synthesis of latanoprost having excellent optical purity (de 99.9%, [α]_D²⁰ = +35.37° (c = 0.90, acetonitrile)) without use of preparative HPLC is described. This process involves effective purification of hydroxyl intermediate (5A) through solvent crystallization followed by inhibition of inversion of the chiral center at C-15 position. This was possible due to judicious use of diol intermediate (6) for double bond reduction prior to hydroxyl protection.

Full text of DOI:10.1080/00397911.2019.1622018

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
An improved synthesis of latanoprost involving
effective control on 15(S) diastereomer
Sachin A. Sasane, Nandu B. Bhise, Girij P. Singh, Alex Joseph & Gautham G.
Shenoy
To cite this article: Sachin A. Sasane, Nandu B. Bhise, Girij P. Singh, Alex Joseph &
Gautham G. Shenoy (2019) An improved synthesis of latanoprost involving effective
control on 15(S) diastereomer, Synthetic Communications, 49:18, 2350-2356, DOI:
10.1080/00397911.2019.1622018
To link to this article: https://doi.org/10.1080/00397911.2019.1622018
Published online: 16 Jul 2019.
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2019, VOL. 49, NO. 18, 2350–2356
https://doi.org/10.1080/00397911.2019.1622018
An improved synthesis of latanoprost involving effective
control on 15(S) diastereomer
Sachin A. Sasanea, Nandu B. Bhisea, Girij P. Singha, Alex Josephb, and
Gautham G. Shenoyb
b
aChemical Research and Development, Lupin Ltd, Mulshi, Pune, India; Department of Chemistry,
Manipal Academy of Higher Education, Manipal, India
ABSTRACT
ARTICLE HISTORY
Received 31 March 2019
An improved process for the synthesis of latanoprost having excel-
20
lent optical purity (de 99.9%, [a]D ¼ þ35.37ꢀ (c ¼ 0.90, acetonitrile))
KEYWORDS
without use of preparative HPLC is described. This process involves
effective purification of hydroxyl intermediate (5A) through solvent
crystallization followed by inhibition of inversion of the chiral center
at C-15 position. This was possible due to judicious use of diol inter-
mediate (6) for double bond reduction prior to hydroxyl protection.
Crystallization; diol
intermediate; ketone
intermediate; latanoprost;
p-nitrobenzoyl chloride;
preparative HPLC
GRAPHICAL ABSTRACT
Introduction
Prostaglandins, a family of biologically endogenous active substances identified and
[1–3]
extensively studied for the treatment of glaucoma.
Out of these, latanoprost (1) is
an important analog structurally related to the PGF2a prostaglandins. Because of the
high efficiency as an anti-glaucoma agent many researchers have been attracted towards
synthesis of this analog. In literature, various methods are reported for the synthesis of
latanoprost.[4] Classical route for the synthesis of latanoprost is presented in
Scheme 1.[5]
CONTACT Sachin A. Sasane
sachinsasane@lupin.com
Chemical Research and Development, Lupin Ltd, Mulshi,
46A/47A, Village Nande, Taluka Mulshi, Pune, Maharashtra, 412115, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Lupin Limited

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Scheme 1. Classical route for latanoprost synthesis
This route involves oxidation of Corey’s lactone (2) followed by Wittig reaction with
dimethyl (2-oxo-4-phenyl butyl) phosphonate to give ketone intermediate (4). Key diol
intermediate (6) was then obtained by stereoselective reduction of (4) to hydroxyl inter-
mediate (5) followed by deprotection and subsequent column chromatographic purifica-
tions. Next step involves protection of diol (6) with different protecting groups and
reduction of double bond to give intermediate (8). Finally, synthesis of latanoprost was
achieved, which involves further stages of DIBAL-H reduction, Wittig reaction with
4-carboxybutyl triphenyl phosphonium bromide followed by esterification using isopro-
pyl iodide and deprotection of the protecting groups. In the patent EP2143712 authors
disclosed process in which intermediate (4) was treated with (-) DIP chloride for reduc-
tion of carbonyl group followed by solvent purification of hydroxyl intermediate (5).
Here, required key diol intermediate (6) was then obtained by deprotection of purified
intermediate (5) having de 89.2%. Subsequently reduction of double bond was achieved
by catalytic transfer hydrogenation method using potassium formate as hydride donor
and 25% Pd/C as a catalyst. Further stages (in Scheme 1) lead to the formation of lata-
noprost in which they have not reported the expected de. In the patent EP0364417
authors disclosed the process in which instead of carbonyl group reduction, intermedi-
ate (4) was subjected to double bond reduction as a key step. According to this method-
ology final stage of purification involves the use of preparative HPLC. Patent
WO02096868A2 discloses process in which hydroxyl intermediate (5) was purified by
column chromatographic purification and utilized for synthesis of latanoprost involving
use of preparative HPLC for purification at final stage. Recently in the patent US2009/

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S. A. SASANE ET AL.
0259066 authors have explained two strategies for synthesis of key intermediate (6).
First one involves stereoselective reduction of triethylsilane (TES) protected ketone
intermediate (4) using (-) DIP chloride followed by in situ deprotection and column
chromatographic purification having de 91.2% for crude diol intermediate (6). In
second strategy they have used dihydropyran (DHP) protecting group instead of TES
keeping rest of the reaction conditions and sequence same to obtain pure diol (6) hav-
ing de 93%. Further, reduction of double bond was carried out using Pd/C under
hydrogen pressure followed by DHP protection to obtain intermediate (8). Latanoprost
20
was then prepared from (8) where specific optical rotation [a]D ¼ þ31.82ꢀ (c ¼ 0.90,
acetonitrile) is disclosed but, expected de for latanoprost is not reported. In the year
1993, Bahram Resul et al. reported the use of lithium selectride for reduction of inter-
mediate (4) which leads to the formation of 7:3 mixture of 15S and 15 R isomer of (5)
even at ꢁ120 ꢀC.
Even after considerable progress made in this field, still existing synthetic routes to
latanoprost by using Corey’s lactone are not having very effective control strategy for
15S diastereomer. In addition, the physicochemical properties of both isomers of latano-
prost (15 R and 15S) are very similar. Hence, it is not a straightforward task to discern
1
between these two compounds by 500 MHz H NMR, optical rotation, or even by ana-
lytical reverse-phase HPLC.[6] Furthermore, the application of preparative scale HPLC
to eliminate (15S) diastereomer is very costly in terms of use of high purity solvents,
chiral columns and far more difficult for production scale. Thus, the method using
Corey’s lactone still have promises to provide perfect approach for effective control of
(15S) diastereomer which will provide the most facile and practical access towards the
synthesis of latanoprost (1). Therefore, a synthesis of latanoprost (1) capable of deliver-
ing the desired product free of its (15S) diastereomer is expected to have considerable
scientific, economic and practical merit in terms of purification circumventing complex
chromatography techniques.
Results and discussion
From above literature, we envisioned that, there could be two potential reasons, which
are accountable for existence of 15S diastereomer in latanoprost. One may be the carry-
over of unwanted diastereomer formed during carbonyl reduction of intermediate (4) if
not purged out properly and another could be inversion at 15 position, as diol (6) is
having allylic hydroxyl group. In order to investigate this hypothesis, we decided to con-
duct some experiments to get latanoprost (1) according to available literature. First we
followed the scheme reported in the patent US2009/0259066. Latanoprost obtained
accordingly contains 3.15% 15S diastereomer (de 93.7%). This validates that, unwanted
isomer formed during carbonyl reduction of (4) does not get purged out during column
chromatography effectively and remains with latanoprost. This is possible because dur-
ing the experimental work we experienced that, there is no difference between Rf values
of 15S and 15 R isomers of latanoprost and its intermediates after hydrogenation of 13,
14-alkene. Hence, removal of unwanted isomer from intermediate (5) is extremely
important to obtain enantiopure latanoprost.

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Scheme 2. Modified route for synthesis of latanoprost
Experiment conducted according to Scheme 1 and by using pure diol (6) (de 99.88%)
had given latanoprost having 1.82% 15S diastereomer. Presence of this 15S diastereomer
confirmed that, there is inversion at 15 position during further reaction. Above experi-
ments conclude that, there should be two control measures during synthesis of latano-
prost. First is effective purification to obtain enantiopure diol intermediate (6) and
second is prevention of inversion at 15 position to save the efforts, cost and chemicals
which were invested in preparation of enantiopure diol (6).
To remove unwanted isomer formed during carbonyl reduction of (4), effective puri-
fication can be achieved through crystallization[7] instead of column chromatography.
Further to overcome the effect of allylic functional group hydrogenation of 13,
14-alkene can be done prior to DHP protection as shown in Scheme 2.
Ketone (4A) was prepared using the procedure reported in reference[8] and isolated
using methanol. Carbonyl group of Ketone (4A) was reduced by using (-) DIP chloride
as disclosed in references.[9] Resulting hydroxyl intermediate (5A) was then converted

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S. A. SASANE ET AL.
into p-nitrobenzoyl protected intermediate (12) and isolated as solid.[7] This was further
[7]
crystallized using toluene in good yield and nitro benzoyl protection was removed
to
give enantiopure diol intermediate (6) having unwanted b isomer 0.06% against 3.50%
according to patent US2009/0259066. Hydrogenation of C-13, C-14 double bond in diol
(6) was then carried out using 10% Pd/C to obtain reduced diol intermediate (13) fol-
lowed by hydroxyl group protection using dihydropyran to get (8A). This intermediate
was then converted to latanoprost (1) through successive reactions of DIBAL-H reduc-
tion, Wittig reaction using 4-carboxybutyl triphenyl phosphonium bromide, esterifica-
tion using isopropyl iodide, deprotection of hydroxyl protecting groups and finally
column purification using acetone and cyclohexane. Chiral HPLC analysis of latanoprost
(1) prepared accordingly, showed 0.05% 15S diasteriomer and specific optical rotation
20
observed is [a]D ¼ þ35.37ꢀ (c ¼ 0.90, acetonitrile).
In this exercise excellent optical purity of latanoprost (1) was obtained due to effect-
ive purification of hydroxyl intermediate (5) and complete inhibition of inversion of the
chiral center at C-15 position. This was possible due to judicious use of dihydroxy
intermediate which does not contain double bond.
Experimental
All solvents were purified and dried by standard procedures prior to use. Reactions
were conducted under atmosphere of nitrogen where ever required. Reactions were
monitored for completion by removing small sample from the reaction mixture and
analyzing by TLC. TLC was performed using acetone: cyclohexane system, visualized
1
under UV short wavelength or using potassium permanganate staining reagent. H and
13C NMR spectra were recorded in CDCl3 using a Bruker 400 and 500 MHz FT NMR
spectrometer, the chemical shifts are reported in d ppm. Chiral HPLC was carried out
using a Shimadzu LC-2010 system with UV detector. Mass spectrometry was carried
out using Waters QDa system. IR analysis was carried out using Perkin spectrum 400.
Specific optical rotation analysis was carried out on Autopol IV, Sr. No. 80646.
Preparation of (3aR,4R,5R,6aS)-5-hydroxy-4-((R)-3-hydroxy-5-
phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one (13)
To the solution of (3aR,4R,5R,6aS)-5-hydroxy-4-((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)hexahydro-2H-cyclopenta[b]furan-2-one (6) (20.0 g, 0.066 mol) in 600 ml ethanol was
added 1 N sodium hydroxide solution (4 ml) and 10% palladium on carbon (50% w/w)
(1 gm). Reaction was carried out at 4 Kg hydrogen pressure at ambient temperature and
monitored by TLC. After reaction completion, mass was filtered to remove catalyst and
pH of was made neutral using 1 N hydrochloric acid. Ethanol was distilled out com-
pletely under vacuum and concentrated mass was purified using column chromatog-
20
raphy to obtain pure intermediate (13) Yield 17 g (85%); [a]D ¼ ꢁ23.83ꢀ (c ¼ 0.35,
acetonitrile); IR (As such): 3626 cmꢁ1, 2860 cmꢁ1, 1747 cmꢁ1 1H-NMR (500 MHz,
;
CDCl3) d (ppm): 1.29 (1 H, m), 1.51–1.58 (3 H, m), 1.77–1.83 (3 H, m), 2.19 (3 H, m),
2.29–2.32 (1 H, m), 2.50–2.54 (2 H, m), 2.68–2.69 (1 H, m), 2.78–2.81 (2 H, m),
3.62–3.63 (1H, m), 4.00–4.01 (1 H, m), 4.95 (1 H, m), 7.20–7.22(3H, m), 7.28–7.32 (2 H,

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dd, J ¼ 10 Hz and J ¼ 3 Hz) 13C NMR (500 MHz, CDCl3): d ppm 177.61, 141.83, 128.49,
128.40, 125.97, 83.90, 77.52, 71.32, 53.94, 43.24, 40.55, 39.11, 35.99, 35.22, 32.05 28.97;
MS: m/z 322.1 (M þ 18 Ammonium adduct); Anal. Calcd for C18H24O4: C, 71.03; H,
7.95; Found C, 71.07; H, 7.92
Conclusion
20
Synthesis of Latanoprost with excellent optical purity (de 99.9%) and [a]D ¼ þ35.37ꢀ
(c ¼ 0.90, acetonitrile) was achieved by purifying intermediate (5) followed by making
use of reduced diol intermediate (13). This method gives easy access to latanoprost hav-
ing (unwanted) 15S isomer less than 0.1% as a chiral impurity, without use of prepara-
tive HPLC.
Acknowledgments
We acknowledge Dr. Arun Natu, Dr. Rajeev Chikate, Dr. Rajesh Vyas and Dr. Himanshu
Godbole for their valuable guidance, support and suggestions. The authors are thankful to analyt-
ical support team for sample analysis. The authors are also thankful to the M/S Lupin Limited
for the research program and Ph.D. registration.
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