Enantioselective Synthesis of ((1 R,2 R)-Cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate, a Lurasidone Hydrochloride Intermediate

Article abstract of DOI:10.1080/00397911.2015.1074695

A concise, economical, and highly enantioselective synthesis of bismesylate intermediate of lurasidone HCl, an antipsychotic, has been developed. The key steps involved in the synthesis are thionyl chloride-catalyzed esterification of tetrahydrophthalic anhydride in MeOH, epimerization of cis to trans isomer, hydrolysis of the diester, resolution of the diacid, reduction with Red-Al, and finally bismesylation of the corresponding diol, which provided the desired intermediate ((1 R,2 R)-cyclohexane-1,2-diyl)bis(methylene) dimethanesulfonate in overall good yield.

Full text of DOI:10.1080/00397911.2015.1074695

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An Enantioselective Synthesis
of ((1R,2R)-Cyclohexane-1,2-
diyl)bis(methylene)dimethanesulfonate, a Lurasidone
Hydrochloride Intermediate
c
ac
a
a
a
b
K. Ravi Ganesh , S. S. Pachore , T. V. Pratap , K. Umesh , M. V. Basaveswarao , C. Murthy &
a
M. Suresh Babu
a
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories
Ltd., Miyapur, Hyderabad, India
b
Department of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh, India
Click for updates
c
Division of Chemistry, Department of Sciences and Humanities, Vignan’ s Foundation for
Science, Technology and Research University (VFSTR Univ.; Vignan University), Vadlamudi,
Guntur, Andhra Pradesh, India
Accepted author version posted online: 24 Aug 2015.
To cite this article: K. Ravi Ganesh, S. S. Pachore, T. V. Pratap, K. Umesh, M. V. Basaveswarao, C. Murthy & M. Suresh Babu
2015): An Enantioselective Synthesis of ((1R,2R)-Cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate, a Lurasidone
(
Hydrochloride Intermediate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI: 10.1080/00397911.2015.1074695
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1074695
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An Enantioselective Synthesis of ((1R,2R)-Cyclohexane-1,2-
diyl)bis(methylene)dimethanesulfonate, a Lurasidone Hydrochloride Intermediate
1
,3
1
1
1
2
K. Ravi Ganesh , S. S. Pachore , T. V. Pratap , K. Umesh , M. V. Basaveswarao , C.
3
1
Murthy , M. Suresh Babu
1
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s
2
Laboratories Ltd., Miyapur, Hyderabad, India, Department of Chemistry, Krishna
University, Machilipatnam, Andhra Pradesh, India, Division of Chemistry, Department
3
of Sciences and Humanities, Vignan’ s Foundation for Science, Technology and Research
University (VFSTR Univ.; Vignan University), Vadlamudi, Guntur, Andhra Pradesh,
India
E-mail: tvpratap@drreddys.com
Abstract
A concise, economical and highly enantioselective synthesis of bis mesylate intermediate
of Lurasidone HCl, an antipsychotic has been developed. The key steps involved in the
synthesis are, thionyl chloride catalyzed esterification of tetrahydro phthalic anhydride in
MeOH, epimerization of cis to trans isomer, hydrolysis of the di ester, resolution of the di
acid, reduction with Red-Al and finally bis mesylation of the corresponding diol provided
the desired intermediate ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene)
dimethanesulfonate in overall good yield.
KEYWORDS: Esterification, Epimerization, Hydrolysis, Resolution, Reduction and
Bis-mesylation.
1

INTRODUCTION
Natural products often inspire synthetic organic chemists, because of their biological
properties and complex structural design. Development of shorter routes to the known
and bioactive natural products via newly established methodologies is of high demand in
modern organic synthesis. Indeed, these strategies allow quicker and economical access
to these compounds for medicinal and other uses. Chiral structures such as 1,2 substituted
cyclo hexane subunits are an integral part of many biologically active compounds
including alkaloids, pharmaceuticals and research probes. The development of synthetic
routes to these structures is often challenging. Considerable efforts have been made in the
recent past both in academia as well as industry for the development of small molecule
based drug discovery program
Trans-1,2-substituted cyclohexane subunit gained the attention of synthetic organic
chemists, as it is the key precursor for the synthesis of various pharmaceutically
important drug substances. Lurasidone. HCl (1) used for the treatment of schizophrenia
and bipolar disorder. The trans-((1R,2R)-cyclohexane-1,2-diyl)dimethanol (2) is the key
intermediate used in the synthesis of Lurasidone. Lurasidone (1), an antipsychotic was
developed by the Japanese firm Dainippon Sumitomo and approved by the U.S. FDA for
the treatment of schizophrenia. The compound showed significant antagonist effects on
[
1]
D2, 5-HT2A, and 5-HT7 receptors which are linked to learning and cognition. In
contrast to available antipsychotics, lurasidone. HCl (1) lacks anticholinergic side effects,
[
2]
giving it an improved safety profile against existing treatments.
2

Lurasidone HCl (1) chemically divided into three components: a piperazine
benzothiazole, a [2.2.1]-bicycloheptane fused succinimide, and a C -symmetric trans-1,2
2
disubstituted cyclohexane (Fig.1). As per the literature reported methods, the large scale
preparation of lurasidone involved an interesting ring-opening alkylation reaction of a
spirocyclic quaternary ammonium derivative (5) . The synthesis commenced with the bis
mesylation of commercially available dimethanol 2, which proceeded in high yield to
[
3, 7]
give dimethane sulfonate 3.
This bis-electrophile 3 underwent dialkylation with
commercially available piperazine 4 under base catalyzed reaction conditions, giving to
[
4]
quaternary ammonium species 5 , isolated in 80% yield as the mono-mesylate salt.
Thus the obtained compound 5 was immediately subjected to alkylative conditions with
[5]
commercially available succinimide 6 to provide lurasidone in 94% yield from 5, and
lurasidone hydrochloride (1) was achieved by subsequent salt formation using
[
6]
hydrochloric acid. Therefore the key intermediate required for the syntheses of
Lurasidone HCl (1) is trans-1,2-substituted cyclohexane subunit (2) and which is further
mesylated to its dimethane sulfonate (3) derivative (Scheme 1).
RESULTS & DISCUSSION
We have been in the development of new strategies and methodologies for various
[8-11]
natural products, API’s and their key intermediates.
After the literature scouting for
the synthesis of dimethanol (2), we have developed an efficient scalable process with the
commercially available and economically benign raw materials. Based on the literature
precedence following methods are utilized for the synthesis of 8, the esterification has
[12]
been carried out using catalytic amount of H SO4 or trimethyl orthoformate and
2
3

alcohol. In general the meso bis ester (8) is subjected to epimerization followed by
[
13]
hydrolysis to provide the racemic diacid. Then the resolution of racemic diacid using
α-methyl benzyl amine provide the trans-diacid with high optical purity. Reduction of
[
14]
trans-diacid using DIBAL-H or LiAlH provide the bis alcohol. According to Jakovac
4
and co-authors the meso alochol was converted to its corresponding chiral γ-lactone using
horse liver alcohol dehydrogenase catalyzed oxidation conditions. Subsequently the
lactone was converted to chiral acid alcohol derivative and finally reduction using LAH
[15]
provided the bis alcohol 3.
Our synthesis of 3 began with thinoyl chloride catalyzed esterification of tetrahydro
phthalic anhydride (7) in presence of MeOH. The obtained meso diester (8) was
subjected to epimerization using catalytic NaOMe in MeOH as solvent to afford the
trans- diester. The diester was subjected to in-situ hydrolysis using NaOH. This
telescopic process helped us in improving the overall yield of 9 & 10 to 87%, over three
steps and obtained the trans-diacid consisting of R,S and R,R isomers (9,10). The
resolution of 9 & 10 was carried out as per the literature methods using a suitable isomer
of α-methyl benzyl amine and obtained the desired R,R isomer of trans-diacid (10) was
purified in MeOH and obtained 25% of yield. Subsequently the optically pure trans-
diacid 10 with R,R configuration was reduced to trans-dimethanol under Red-Al reaction
conditions using toluene as solvent. The dimethanol 2 was purified using DCM and n-
hexane and obtained as an off-white color solid in 82% yield. The obtained trans-bis
alcohol 2 was then converted to dimethane sulfonate 3 under the reported conditions
using TEA and MsCl and obtained the product 3 in 92% yield and 99.4% ee (Scheme 2).
4

In Summary, we have established a simple, convenient and economically benign process
for 3 and achieved overall good yield and high ee. Also developed the analytical methods
for this non UV active intermediates using RI detector in both chemical and chiral
methods.
EXPERIMENTAL
General methods: All reactions were carried out in oven dried glassware under an
1
13
atmosphere of N H & C NMR spectra were recorded in CDCl & DMSO-d on
2
.
3
6
Varian Gemini 400 MHz FT spectrometers. Proton chemical shifts (δ) are relative to
tetramethylsilane (TMS, δ 0.00) as internal standard and expressed in ppm. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet) and m (multiplet). Coupling
constants (J) are given in Hertz. Mass spectra were obtained on a HP-5989A Mass
Spectrometer. Thin layer chromatography was performed on silica gel plates (SRL 230-
4
00 mesh). All solvents used are commercially available and were distilled before use.
Synthesis Of (1R,2R)-Cyclohexane-1,2-Dicarboxylic Acid And (1R,2S)-Cyclohexane-
,2-Dicarboxylic Acid (9 & 10)
1
SOCl (15.45 g, 129.8 mmol) was added to a mixture of cis-1, 2-
2
cyclohexanedicarboxylic anhydride (200 g, 1298 mmol) and methanol (1400 mL) at 20
°
C. The reaction mass was refluxed for 3 - 4 h. Methanol was concentrated completely
and residue was diluted with MTBE 1000 mL and sodium bicarbonate solution was
added to it. Organic layer was separated and was washed with water and brine solution.
5

Organic layer was distilled completely to furnish 8. The residue was dissolved in fresh
methanol (1040 mL) and added sodium methoxide (28 g, 519.4 mmol). The reaction
mass was refluxed for 4 h and methanol was distilled completely under reduced pressure.
To the residue 13% aq. NaOH solution (2000 mL) was added. Reaction mass was
maintained for 3 - 4 h at 75 °C and cooled the reaction mass to 0-5 °C. The reaction mass
pH was adjusted to 2.0 at 0 - 5 °C with concentrated HCl (900 mL). The obtained solid
was filtered and wet cake was washed with excess water (1500 mL) and dried under
reduced pressure to give a white solid. Yield: 87%. HRMS (ESI TOFMS): calcd. for
C H O Na, 173.0814; found, 173.0821; HPLC Conditions: Chemical: Column: Zorbax
8
12
4
SB CN (150 * 4.6 mm) * (3.5µ), Mobile phase: A: 0.1% H PO in H O, M.P. B: ACN,
3
4
2
Purity by HPLC (Area under curve): 94.3% (trans) retention time: 6.98 and 2.1% (cis)
retention time: 7.579; Chiral: Column: Chiral PAK IC (250 x 4.6 mm) 5.0 µm, Mobile
phase: n-Hexane: IPA : TFA (950 : 50l : 1), Diluent : Methanol :mp (1:1), Flow rate:
1
.0mL/min, Column temp: 25°C, Inj. vol: 10 µl. Wave length: 210 nm. Purity by HPLC
(area under curve) 40.35% (R,S Isomer) retention time 16.065 and 56.18% (R,S Isomer)
retention time 20.269.
Synthesis Of (1R,2R)-Cyclohexane-1,2-Dicarboxylic Acid (10)
R-(+)-Phenyl ethyl amine (11) (35.25 g, mL 290.69 mmol) was added to a solution of
trans racemic mixture of trans diacid (9 & 10) (50.0 g, 290.69 mmol) in methanol (150.0
mL) at 0 °C. Mixture was stirred about 30 mins. and then stirred for 3 h at 25 – 35 °C.
Reaction mixture was cooled to -5 to 0 °C and stirred for 1 h then filtered. Dried the solid
under suction and obtained 30 g of wet compound. The wet compound and MeOH (90.0
6

mL) charged in RBF and heated to 65 °C. Maintained under stirring at same temperature
for 2h and mixture was cooled to -5 °C then it was stirred for 2h and filtered. The
obtained compound was suspended in 1N HCl (345 mL) and extracted with ethyl acetate
(2X 230 mL). Organic layer was separated and concentrated to dryness under reduced
1
pressure to obtain white color solid. Yield: 25%. H-NMR (DMSO d , 400MHz): δ 12.06
6
1
3
(
s, 1H), 2.35 (s, 1H), 1.92 (s, 1H), 1.69 (s, 1H), 1.23 (s, 2H). C-NMR (DMSO d ,
6
4
1
00MHz): 175.1, 41.8, 26.1, 23.6. HRMS (ESI TOFMS): calcd. for C H O Na,
8 12 4
73.0814; found, 173.0821. HPLC Conditions: Chemical: Column: Zorbax XDB C8
(
250* 4.6 mm)* (3.5µ), Column Temp. 40 °C, RID,: Sensitivity: 65, RID temp.: 35 °C,
Run time 40 Min, Flow : 0.8 mL/min. Purity by HPLC (AUC): 99.83% retention time
.831. Chiral: Column: Chiral PAK IC (250 x 4.6 mm) 5.0 µm, Mobile phase: n-Hexane :
4
IPA : TFA (950 : 50l : 1), Diluent : Methanol :mp (1:1), Flow rate: 1.0mL/min, Column
temp: 25 °C, Inj. vol: 10 µl. Wave length: 210 nm. Purity by HPLC (area under curve)
1
00% (R,R Isomer) retention time 9.331.
Synthesis Of ((1R,2R)-Cyclohexane-1,2-Diyl)Dimethanol (2)
Red-Al (70% solution in Toluene) (134 g, 460 mmol) was added to solution of 10 (16 g,
9
3 mmol) in THF (160 mL) at 0-5 °C under nitrogen atmosphere. Reaction mixture was
refluxed for 5 h and mixture was cooled to 0 – 5 °C and then added 20% aq. NaOH
solution (320 mL). Reaction temperature was allowed to room temperature and stirred for
1
h. It was extracted with toluene and organic layer was concentrated to dryness under
reduced pressure and residue was cooled to 0 – 5 °C. DCM (2.4 mL) and n-hexane (40
mL) were added to the residue and stirred at 0-5 °C for 30 minutes and filtered to obtain
7

1
off-white color solid. Yield: 85.2%. H-NMR (DMSO d , 400MHz): δ 4.37 (t, J = 4.8Hz,
6
1
H), 3.49-3.33 (m, 1H), 3.31-3.26 (m, 1H), 1.71-1.63 (m, 2H), 1.21-1.11 (m, 2H), 1.04 (t,
1
3
J = 11.2Hz, 1H). C-NMR (DMSO d , 400MHz): 64.5, 42.1, 29.6, 26.0. HRMS (ESI
6
TOFMS): calcd. for C H O Na, 145.1229; found, 145.1226. HPLC conditions: Column:
8
16
2
Column: Zorbax XDB-C8 (250*4) mm, 3.5µm, Column temp: 40 °C, RID: Sensitivity:
6
9
5, RID temp.: 35 °C, Run time: 40 min, Flow: 0.8 ml/min. Purity by HPLC (AUC):
9.28% retention time 5.182.
Synthesis Of ((1R,2R)-Cyclohexane-1,2-Diyl)Bis(Methylene) Dimethanesulfonate (3)
Methane sulfonyl chloride (12 mL, 150 mmol) was added to a mixture of 2 (10 g, 69
mmol) in DCM (100 mL) and TEA (25.0 mL, 170 mmol) at 0 – 5 °C. It was then allowed
to room temperature. Reaction mixture was stirred for 2 h and diluted with DCM (50
mL). Compound was extracted into DCM and washed with water and dried over anhyd.
Na SO . DCM layer was distilled under reduced pressure and the obtained crude
2
4
2
0
compound was further purified using n-hexane (100 mL). Yield: 92%, [ ]D = -27.5°
2
4.5
[16] 1
(
C=4%, Benzene at 20 °C); lit. [ ]D = -29.2° (C=4%, Benzene at 20 °C).
H-NMR
(
CDCl , 400MHz): δ 4.35 (d, J = 10Hz, 1H), 4.18 (d, J = 10Hz, 1H), 3.03 (s, 3H), 1.82-
3
1
3
1
3
3
.78 (m, 2H), 1.71 (m, 1H), 1.29-1.27 (m, 2H). C-NMR (DMSO d , 400 MHz): 72.1,
6
7.0, 36.3, 28.3, 24.7. HRMS (ESI TOFMS): calcd. for C H O S Na 301.0780; found,
1
0
20
6 2
01.0778. HPLC conditions: Chemical: Column: Zorbax XDB-C8 (250*4) mm, 3.5µm,
Column temp: 40 °C, RID: Sensitivity: 65, RID temp: 35 °C, Run time: 40 min, Flow:
.8 ml/min. HPLC (AUC): 99.10% retention time 18.041, Chiral: Column: Chiral PAK
0
IC (250 x 4.6 mm) 5.0 µm. Mobile phase: n-Hexane : IPA : EtOH : DEA (650 : 200 : 150
8

:
5), Column temp : 27°C, Flow: 1.0 ml/min, Inj. 10 µl. Purity by HPLC: 99.71 (R,R
Isomer) retention time 24.566 and 0.28% (R,S isomer) retention time 23.005;
Enantiomeric excess (ee): 99.43%.
ACKNOWLEDGEMENTS
The authors K. R. Ganesh and S. B. Meruva would like to thank Dr. Vilas H. Dahanukar
and Dr. H. Rama Mohan of Dr. Reddy’s Laboratories Ltd. for their encouragement.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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1
1

Scheme 1. Synthetic scheme for Lurasidone HCl (1).
1
2

Scheme 2. Synthetic scheme of Bis mesylate (3)
1
3

Figure 1
1
4