Stereoselective synthesis of the optical isomers of a new muscarinic receptor antagonist, HL-031120

Article abstract of DOI:10.1080/00397910600602453

We present here a practical stereoselective synthetic method to produce enantiopure isomers of a new muscarinic receptor antagonist, HL-031120 (3-quinuclidinyl-2′-cyclopentyl-2′-hydroxy-2′-phenylacetate, I). Four optical isomers were effectively by stereoselective synthesized using pivaldehyde as steric hindrance agent from the chiral starting material, ( S ) or ( R )-mandelic acid. The isomers were obtained with 70-76% yields in 98-99% e.e. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600602453

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Stereoselective Synthesis of the Optical
Isomers of a New Muscarinic Receptor
Antagonist, HL‐031120
Yu‐Min Liu a , He Liu b , Bo‐Hua Zhong b & Ke‐Liang Liu b
a College of Chemical and Pharmaceutical Engineering , Hebei University of
Science and Technology , Shijiazhuang, China
b No. 7 Department , Beijing Institute of Pharmacology and Toxicology ,
Beijing, China
Published online: 18 Aug 2006.
To cite this article: Yu‐Min Liu , He Liu , Bo‐Hua Zhong & Ke‐Liang Liu (2006) Stereoselective Synthesis of
the Optical Isomers of a New Muscarinic Receptor Antagonist, HL‐031120, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:13, 1815-1822, DOI:
10.1080/00397910600602453
To link to this article: http://dx.doi.org/10.1080/00397910600602453
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Synthetic Communicationsw, 36: 1815–1822, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602453
Stereoselective Synthesis of the Optical
Isomers of a New Muscarinic Receptor
Antagonist, HL-031120
Yu-Min Liu
College of Chemical and Pharmaceutical Engineering, Hebei University
of Science and Technology, Shijiazhuang, China
He Liu, Bo-Hua Zhong, and Ke-Liang Liu
No. 7 Department, Beijing Institute of Pharmacology and Toxicology,
Beijing, China
Abstract: We present here a practical stereoselective synthetic method to produce
enantiopure isomers of a new muscarinic receptor antagonist, HL-031120 (3-quinucli-
dinyl-20-cyclopentyl-20-hydroxy-20-phenylacetate, I). Four optical isomers were effec-
tively by stereoselective synthesized using pivaldehyde as steric hindrance agent from
the chiral starting material, (S) or (R)-mandelic acid. The isomers were obtained with
70–76% yields in 98–99% e.e.
Keywords: Muscarinic receptor antagonist, stereoselective synthesis, tertiary a-
hydroxy acid
INTRODUCTION
Design, development, and marketing of new chiral active substances are now
major themes in drug research and industry.[1] Awareness and interest in the
stereochemistry of drug action have increased, and the worldwide sales of
chiral drugs in single-enantiomer form continues to grow. In January 1996,
the Food and Drug Administration (FDA) announced it would consider
Received in China October 2, 2005
Address correspondence to He Liu, No. 7 Department, Beijing Institute of Pharma-
cology and Toxicology, 27 Taiping Road, Beijing 100850, China. Fax: þ86-10-
68211656;. E-mail: hliuamms@yahoo.com
1815

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Y.-M. Liu et al.
further incentives for developing single isomer drugs, owing to their better
pharmacokinetics prosperity, safety, and tolerability. Over the past century,
classical anticholinergic drugs have been widely used for the treatment of
certain diseases, such as chronic obstructive pulmonary disease (COPD),
Alzheimer’s disease, and urinary incontinence. Most of the muscarinic
receptor antagonists have a chiral tertiary a-hydroxy acid as a key
component.[2] However, their therapeutic use was limited, because of side
effects in both the peripheral and central nervous system.
We have been engaged in the synthesis and study of the biological activity
of anticholinergic drugs for many years.[3] A novel muscarinic receptor
antagonist, HL-031120 (3-quinuclidinyl-20-cyclopentyl-20-hydroxy-20-pheny-
lacetate I, Chart 1), was synthesized. The receptor binding assay showed that
this compound had far greater selectivity for M3 over the M1 receptor subtype,
which makes it potentially useful in the treatment of respiratory disorders such
as COPD. I is composed of an ester bond as a linkage connecting the two parts,
that is, a tertiary hydroxyl structure and the azepine base substituent. There are
two chiral carbon atoms in I that should have four optical isomers. Preliminary
biological results suggest that (3R,20R)-I displays, an improved therapeutic
profile compared to its racemic counterpart.
Diastereoselective synthesis of the enantiomers of I was performed as
outlined in Scheme 1 [(R)-mandelic acid as a example]. The preparation of
high-yielding and highly diastereoselective acetal (2R,5R)-1 from mandelic
acid was readily accomplished and is practical and amenable to scaling. Depro-
tonation of pure 1 with lithuium bis(trimethylsilyl) amide (LHMDS) followed
by the addition of cyclopentanone affords the aidolate (2R,5R)-2. The hydroxy
group of 2 can easily be eliminated using the simple reagents SOCl2/pyridine
to give lactone (2R,5R)-3, and then hydrogenation of the double bond can
obtain (2R,5R)-4. (R)-a-Hydroxy-a-cyclopentyl-a-phenylacetic acid 5 was
produced by hydrolysis of 4. Then 5 reacted with CH2N2 to obtain methyl
(R)-a-hydroxy-a-cyclopentyl-a-phenylacetate 6. Compound (3R,20R)-I was
synthesized by (R)-6 with (R)-3-quinuclidinol. Other isomers were synthesized
with the same method as described for (3R,20R)-I from the starting material, (S)
or (R)-mandelic acid and (S) or (R)-3-quinuclidinol. The final step involved the
ring opening of chiral ester with alcohol, which could readily be performed by
simple nucleophile substitution with NaH in n-heptane, and the results are
Chart 1.

HL-031120, New Muscarinic Receptor Antagonist
1817
Scheme 1.
shown in Table 1. The data in Table 1 show that the enantiopure isomers of I
were obtained in moderate yields with high e.e. values by using our synthetic
method. Crystals of the (3R,20R)-I suitable for X-ray structure determination
were obtained by slow evaporation of its CH2Cl2 solution. The crystal
structure of the (3R,20R)-I with atomic labeling is shown in Figure 1.
The isomers of 3-quinuclidinol were resoluted according to the method[4]
shown in Scheme 2. The racemic 3-quinuclidinol was reacted with
(CH3CO)2O at 1608C for 3 h to give acetate, which reacted with L-(þ)-
tartaric acid to form tartaric acid salt. After being recrystallized in 80%
EtOH four times, the salt reacted with 2N NaOH at 758C for 2 h, and then
the solution was saturated with anhydrous K2CO3 and extracted with
benzene at 758C give (R)-3-quinuclidinol in 63% yield. Similarly, (S)-3-qui-
nuclidinol could be obtained with D-(-)-tartaric acid as the resolution agent.
EXPERIMENTAL
All the reagents were commercially available, used without further purifi-
cation, or purified by standard methods prior to use. Melting points were deter-
1
mined using a RY-1 apparatus and are uncorrected. H NMR spectra were

Table 1. Synthetic results of the four isomers of I
Entry
6
3-Quinuclidinol
I
E.e. (%)a
Yield (%)b
(3R,20R)-I
98.1
70
(3S,20R)-I
98.5
72
(3R,20S)-I
(3S,20S)-I
99.3
99.2
75
76
aThe e.e. is determined by HPLC (Chiradex Cartridge, mobile phase 40% acetonitrile/60% 0.05M KH2PO4/0.1% Et3N at pH 6.5.
bYield of the reaction between ester 6 and 3-quinuclidinol.

HL-031120, New Muscarinic Receptor Antagonist
1819
Figure 1. Crystal structure of the (3R,20R)-I.
recorded on JNM-ECA-400 400-MHz instrument in the solvent indicated.
Chemical shift values are reported in parts per million (ppm) relative to tetra-
methylsilane, used as an internal reference standard. Mass spectra were
obtained from Micromass ZabSpec and API3000 instruments. Elemental
analysis was carried on the CarloErba-1106. All reactions were monitored
by TLC on 25 ꢀ 75-mm glass sheets precoated with silica gel (GF254) to a
thickness of 0.25 mm and viewed at 254-nm UV light. Four isomers were syn-
thesized in the same method as described for (3R,20R)-I from the starting
material, (S) or (R)-mandelic acid.
(2R,5R)-2-(tert-Butyl)-5-phenyl-1,3-dioxolan-4-one (1)
(S)-mandelic acid (7.6 g, 50 mmol) and pivaldehyde (6.5 mL, 60 mmol) were
dissolved in 100 mL of pentane, followed by addition of trifluoromethanesul-
fonic acid (0.15 mL, 1.8 mmol) at 208C. The mixture was warmed to 368C and
allowed to reflux for 6 h and then allowed to cool to room temperature.
Aqueous NaHCO3 (5%) was added. The mixture was concentrated in vacuo
to remove pentane. Compound 1 was obtained by filtering the slurry, 10.1 g
Scheme 2.
.

1820
Y.-M. Liu et al.
(91%). Anal. calcd. for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.81; H, 7.40.
1H NMR (CDCl3): d 7.45 (m, 5H), 5.31 (s, 1H), 5.25 (s, 1H), 1.10 (s, 9H).
(2R,5R)-2-(tert-Butyl)-5-phenyl-5-(cyclopentyl-1-ol)-1,3-dioxolan-4-
one (2)
A homogenized mixture of lithium bis(trimethylsilyl) amide (100 mL,
100 mmol, 1.0 M in hexanes) and 1 (20.0 g, 91 mmol) was added in 500 mL
of THF at 2708C. The reaction mixture was stirred for 1 h, followed by the
addition of cyclopentanone (11 mL, 120 mmol). After stirring for 3 h, a
saturated NaHPO4 solution (50 mL) was added. The reaction mixture was
poured into the saturated NH4Cl solution (300 mL). The aqueous layer was
separated and extracted with ethyl acetate. After being concentrated in a
vacuum, 2 was obtained as a white solid, 21.5 g (67%). Anal. calcd. for
1
C18H24O4: C, 71.03; H, 7.95. Found: C, 70.91; H, 7.90. H NMR (CDCl3):
d 7.76 (m, 2H), 7.35 (m, 3H), 5.54 (s, 1H), 1.55–2.10 (s, 8H), 0.92 (s, 9H).
(2R,5R)-2-(tert-Butyl)-5-phenyl-5-(cyclopentyl-1-ene)-1,3-dioxolan-
4-one (3) and (2R,5R)-2-(tert-Butyl)-5-phenyl-5-cyclopentyl-1,3-
dioxolan-4-one (4)
Compound 2 (15.2 g, 50 mmol) was dissolved in THF (300 mL), followed by
the addition of thionyl chloride (10 mL, 130 mmol) and pyridine (9 mL,
11 mmol) at 08C. The reaction mixture was allowed to stir for 3 h at 08C,
followed by the addition of saturated NH4Cl solution (300 mL). The
aqueous layer was separated and washed with ethyl acetate (100 mL ꢀ 3).
The combined organic layers were dried (anhydrous Na2SO4), filtered, and
concentrated in vacuo to give 3. The crude product 3 was not separate, and
further purification was needed. Methanol (500 mL) and 0.8 g of 10% Pd/C
was added. The reaction was subjected to 1 atm of hydrogen and was
allowed to stir for 10 h. The reaction mixture was filtered through a plug of
Celitew and washed with 50 mL of methanol. The solution was concentrated
in vacuo to provide 4, 12.5 g (87%). Anal. calcd. for C18H24O3: C, 74.97;
1
H, 8.39. Found: C, 74.81; H, 8.45. H NMR (CDCl3): d 7.59 (m, 1H), 7.25
(m, 4H), 6.03 (m, 1H), 5.22 (s, 1H), 1.91–2.50 (m, 8H), 1.07 (s, 9H).
(R)-a-Cyclopentyl-a-hydroxyl-a-phenylacetic Acid (5) and
(R)-Methyl-a-cyclopentyl-a-hydroxy-a-phenylacetate (6)
Water (10 mL) and solid KOH (4.0 g, 100 mmol) were added to a solution of 4
(2.8 g, 10 mmol) in methanol (10 mL). The reaction was allowed to reflux for
3 h. After cooling to room temperature, the reaction mixture was washed with

HL-031120, New Muscarinic Receptor Antagonist
1821
heptane (50 mL ꢀ 2). The aqueous layer was acidified to pH 1 with 1 N HCl,
and the resulting mixture was extracted with ethyl acetate (50 mL ꢀ 3). The
combined organic layers were dried (Na2SO4), filtered, and concentrated in
vacuo to give (R)-a-(cyclopentyl-1-ene)-a-hydroxyl-a-phenylacetic acid 5.
The crude product 5 was not separate and further purification was neded. It
was treated with a solution of CH2N2 in Et2O (about 300 mmol); the
mixture was stirred at room temperature for 30 min and concentrated in
vacuo to provide 6, 2.5 g (95%). MS (ESI): 235.2 (M þ 1); 1H NMR
(CDCl3): d 7.53 (m, 2H), 7.32 (m, 3H), 5.62 (s, 1H), 3.80 (m, 3H), 2.40
(m, 4H), 1.90 (m, 2H). 13C NMR (CD3Cl), d 176.07, 141.65, 127.98,
127.32, 125.82, 79.15, 53.11, 47.16, 26.85, 26.26, 26.20, 25.85.
(3R,20R)-3-Quinuclidinyl-20-cyclopentyl-20-hydroxy-20-
phenylacetate ((3R,20R)-I)
Compound 6 (2.35 g, 10 mmol) and (R)-3-quinuclidinol (0.95 g, 9 mmol) were
dissolved in anhydrous n-heptane (100 mL); NaH (0.5 g, assay 80%) was
added. The solution was refluxed for 4 h. The solvent was removed under
reduced pressure; the residue was dissolved in ether (100 mL), washed with
water and brine, dried over anhydrous sodium sulfate, and concentrated to
dryness. The product was purified by flash chromatography, and (3R,20R)-I
was isolated as an white solid (2.1 g, 70%). Mp: 121–1238C. 1H NMR
(CDCl3): 7.56 (2H, m), 7.32 (3H, m), 5.69 (1H, s), 4.91 (1H, s), 3.99
(s, 1H), 3.16 (m, 1H), 2.75 (m, 5H), 2.05 (s, 1H), 1.91–1.70 (m, 9H) 1.55
(m, 1H), 1.39 (m, 2H). 13C NMR d (CDCl3), 173.92, 144.47, 140.06,
127.94, 127.81, 126.46, 79.50, 73.71, 55.10, 47.11, 46.24, 32.53, 32.05,
25.25, 24.29, 23.48, 19.49. ESI-MS: 330.2 (M þ 1). Anal. calc. for
C20H27NO3: C, 72.92; H, 8.26; N, 4.25; found: C, 72.88; H, 8.31; N, 4.22.
ACKNOWLEDGMENT
We are gratefully acknowledge financial support from the National Natural
Science Foundation of China (No. 203900508).
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