Synthesis of tetracyclic heterocompounds as selective estrogen receptor modulators. Part 3. Development of an acid-catalyzed racemization process for (s)-2,8-(dimethoxy)-5-{4-[2-(1-piperidinyl)ethoxy]-phenyl}-11,12-dihydro-5H-6, 13-dioxabenzo[3,4]cyclohep

Article abstract of DOI:10.1021/op800237y

A novel and economical process was developed for recycling the undesired enantiomer, (S)-2,8-dimethoxy-5-{4-[2-(1-piperidinyl)-ethoxy]phenyl}-11,12- dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta[1,2-α]naphthalene (1b) obtained from chiral chromatographic sepa

Full text of DOI:10.1021/op800237y

Organic Process Research & Development 2009, 13, 102–105
Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor
Modulators. Part 3. Development of an Acid-Catalyzed Racemization Process for
(
S)-2,8-(Dimethoxy)-5-{4-[2-(1-piperidinyl)ethoxy]-
phenyl}-11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene
,
†
†
§
‡
§
§
§
Xun Li,* Ronald K. Russell, Andr a´ s Horv a´ th, Nareshkumar Jain, Dominique Depr e´ , Dominic Ormerod, Wim Aelterman,
‡
and Zhihua Sui
Johnson & Johnson Pharmaceutical Research and DeVelopment, L.L.C., U.S. East Coast Research and Early DeVelopment,
1
000 Route 202, Raritan, New Jersey 08869, U.S.A., and Johnson and Johnson Pharmaceutical Research and DeVelopment,
A DiVision of Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium
Abstract:
although it was known that the very similar (R)-3-(4-hydrox-
A novel and economical process was developed for recycling the
undesired enantiomer, (S)-2,8-dimethoxy-5-{4-[2-(1-piperidinyl)-
ethoxy]phenyl}-11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclohep-
ta[1,2-a]naphthalene (1b) obtained from chiral chromatographic
separation, by refluxing 1b with HCl (4.0 equiv) in EtOH for 76 h,
yphenyl)-4-methyl-2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2H-
chromen-7-ol (2a, Scheme 2), a 2,3,4,7-substituted coumarin
derivative, could be easily converted to a racemic mixture in
92% yield, after treatment with 5% LiOH in DMF at 80 °C for
3
4
3 h. Due to the similarity, compound (R)-3a (99.0% ee), the
2,8-dihydroxy analogue of (R)-1a, was first subjected to these
known base-catalyzed conditions (5% LiOH in DMF at 80 °C)
to produce a 63.3% (R)-3a enriched mixture after 60 h. The
rate slowed unacceptably toward the end of the reaction, and
no further optimization was conducted with LiOH-catalyzed
racemization of (R)-3a.
2 4
or with H SO (2.0 equiv) in water for 68 h to afford a near
racemic mixture ((R)-1a/(S)-1b ) 41-42%/49-53%, chiral
HPLC area%) in >96% isolated yield and good chemical
purity (87-95%).
Introduction
When the above LiOH-catalyzed conditions were applied
to pure 2,8-dimethoxy (R)-1a enantiomer (99.8% ee), however,
no product (S)-1b was detected in the reaction mixture as
analyzed by chiral HPLC. In addition, the treatment of (R)-1a
separately with other bases (such as KOH, piperidine, and
The scale-up preparation of 2,5,8-substituted 11,12-dihydro-
5H-6,13-dioxabenzo[3,4]cyclohepta-[1,2-a]naphthalene deriva-
tives as selective estrogen receptor modulators (SERMs) has
been reported recently, where racemate 1 was prepared via an
1
eight-step nonchromatographic linear synthetic process in 17%
overall yield with 99.5% chemical purity (RPHPLC, area %).
Chiral HPLC separation of 1 afforded (R)-enantiomer 1a and
the corresponding (S)-enantiomer 1b (Scheme 1). Furthermore,
the advanced in Vitro and in ViVo biological studies determined
that (R)-1a was the most active compound with the desired
SERM activity, while (S)-1b was the enantiomer with weak
SERM activity. Because attempts for either enantioselective
asymmetric synthesis of (R)-1a or the enantiomeric resolution
4
-(N,N-dimethyl)pyridine) in different refluxing solvents (such
as MeOH, EtOH, and MeCN) also did not result in (S)-1b. It
seemed that a base deprotonation of 2- and/or 8-phenolic
hydroxyl group (calculated pK s of 2-OH and 8-OH ) 10.19
and 9.88, respectively) of (R)-3a was the driving force for this
base-catalyzed racemization. The enantiomer (R)-1a was unable
to be racemized under investigated basic conditions because of
having 2,8-dimethoxy groups on the molecule.
The unsuccessful racemizations of (R)-1a/(S)-1b under basic
conditions led us to explore other possible chemistries. For
instance, (R)-1a/(S)-1b could possibly be racemized under acid-
a
1
2
of the racemate 1 with chiral acids were unfruitful, the optically
pure (>99% ee) (R)-1a was obtained on kilogram scale by the
chiral chromatographic separation of racemate 1. The conversion
of (S)-1b back to the racemic 1 would help in a higher yield of
5
catalyzed conditions when more than one equivalent of an acid
was used, due to the presence of the piperidine ring on the side
(R)-1a within a short time cycle. Herein, we report an acid-
catalyzed racemization process for recycling (S)-1b.
(
(
3) Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre, A.; Larouche,
D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger, A.; Leblanc, G.; Martel,
C.; Simard, J.; Merand, Y.; Belanger, A.; Labrie, C.; Labrie, F. J. Med.
Chem. 1997, 40, 2117.
Results and Discussion
A review of the literature showed no published results on
the racemization of a tetracyclic compound like (R)-1a/(S)-1b,
4) The optically pure (99.0% ee) (R)-enantiomer 3a was obtained from a
preparative chiral HPLC separation of its racemate 3, which was
prepared in-house and described as compound 11 in ref 1a of this
publication.
*
Author for correspondence. Telephone: (908)707-3321. Fax: (908)526-6469.
E-mail: xli6@its.jnj.com.
(5) (a) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44, 4051. (b)
Cheng, K.; Liang, G.; Hu, C. Molecules 2008, 13, 938. (c) Zhang, L.-
H.; Gupta, A. K.; Cook, J. M. J. Org. Chem. 1989, 54, 4708.
(6) (a) Stahl, P. H.; Wermuth, C. G., Eds. Handbook of Pharmaceutical
Salts Properties, Selection, and Use; Wiley-VCH: Z u¨ rich, Switzerland,
2002; Vol. 28, p 75. (b) Stahl, P. H.; Wermuth, C. G., Eds. Handbook
of Pharmaceutical Salts Properties, Selection, and Use; Wiley-VCH:
Z u¨ rich, Switzerland, 2002; Vol. 28, pp 9-290. (c) Leuches, M.; Zundel,
G. Can. J. Chem. 1980, 58, 311.
†
High Out Put Synthesis, EC RED, U.S.A.
Medicinal Chemistry Team VI, EC RED, U.S.A.
API Development, Janssen Pharmaceutica, Belgium.
‡
§
(
1) (a) Li, X.; Reuman, M.; Russell, R. K.; Youells, S.; Beish, S.; Hu, Z.;
Branum, S.; Jain, N.; Sui, Z. Org. Process Res. DeV. 2007, 11, 731.
(b) Kanojia, R. M.; Jain, N. F.; Ng, R.; Sui, Z.; Xu, J. WO2003053977,
2
003.
(
2) Unpublished internal communications.
1
02
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development
10.1021/op800237y CCC: $40.75  2009 American Chemical Society
Published on Web 12/31/2008

Scheme 1
Scheme 2
Scheme 3
a near racemic mixture with the presence of 4b (7.5%)
under the above-described HCl-catalyzed conditions (entry
9
of Table 1). On the other hand, although the reaction of
(
S)-1b with 4.0 equiv of aqueous HCl (37% solution) in
chain of (R)-1a or (S)-1b. The excess acid could protonate the
molecule on oxygen, preferably the 6-oxygen, to form a
refluxing water for about three days that resulted in only
trace amount (<1%) of (R)-1a (entry 13 of Table 1),
H
5
delocalized oxonium species, which might cause the C ste-
5a
6c
reogenic center to be racemized.
2
SO
4
(2.0 equiv) (pK
a
) -3.0) still accomplished a
To test this hypothesis, (S)-1b (98.6% ee) was treated
with a slight excess (1.13 equiv) of either (1R)-(-)- or
near racemic mixture under the same reaction conditions
(entry 14 of Table 1). Considering HCl is a very strong
Brønsted acid, other commonly used Lewis acids such as
BF · Et O, MgBr · Et O, SnCl , and TiCl were also
examined for catalyzing the racemization of (S)-1b, all
which, however, resulted in less than 10% of the desired
enantiomer (R)-1a under the investigated conditions
(
)
1S)-(+)-10-camphorsulfonic acid ((-)-/(+)-CSA) (pK
-2.17) in refluxing EtOH for 60 h; both reactions
a
6
a
3
2
2
2
4
4
gave very similar (S)-1b-enriched (∼68.5%, chiral HPLC
area %) mixtures with the formation of (R)-1a (∼29%)
7
and a detectable level of byproduct 4b (∼2.3%) (Scheme
3
, entries 1 and 2 of Table 1). Other solvents (such as
(
entries 15-20 of Table 1). The above HCl-catalyzed
reaction conditions were found to be reproducible on 1-,
0-, and 30-g scale of (S)-1b, which set the stage for
CH
EtOH was selected, which showed either no racemization
for example, in CH Cl and MeCN) or less than 10%
2 2
Cl , MeCN, THF, and MeOH) were screened before
1
(
2
2
racemization on larger scale. This acid-catalyzed process
was not conducted on multikilogram scale because the
project was unforeseeably terminated before the scale-up
campaign.
A proposed reaction mechanism for this acid-catalyzed
racemization of (S)-1b is shown in Scheme 4. After the
formation (in THF and MeOH) of (R)-1a, after (S)-1b (1.0
equiv) was refluxed with (1R)-CSA (1.13 equiv) in each
tested solvent for 60 h, respectively. Among all acids
tested, the best result (42.0% of (R)-1a) was achieved
when only HCl (4.0 equiv, 1 M solution in EtOH) (pK
a
6
b,c
)
-6.0 and -6.1) was used after 76 h (entry 8 of Table
6
5
C
-oxygen of (S)-1b was protonated to the oxonium intermediate
, the positive charge could delocalize the electron density on
-O bond via path a that led to the stabilized 4,5,8-
trisubstitued-2,3-dihydrobenzo[b]oxepine carbocation intermedi-
1
), extending the reaction time to 96 h did not change the
product profile. Of interest, (R)-1a was also converted to
5
6
1
(
7) The structure of the byproduct 4b was confirmed by comparing its H
+
NMR, LC/MS (MH ) 514), and HPLC analytical data with an in-
8
a
ate 4a, of which the 4-substituted phenol hydroxyl group could
approach to the sp hybridized carbocation carbon from either
the top or bottom side and reclose the B-ring to achieve a
house prepared authentic compound 4b.
2
8b
(
8) (a) March, J. AdVanced Organic Chemistry: Reaction, Mechanisms, and
Structure, 4th ed.; John Wiley & Sons, Inc.: New York, U.S.A., 1992;
Vol. 16, pp 5-174. (b) Laube, T. Angew. Chem., Int. Ed. Engl. 1986,
5
2
5, 349.
racemic (R)-1a/(S)-1b mixture. On the other hand, the syn-
Vol. 13, No. 1, 2009 / Organic Process Research & Development
•
103

Table 1. Results of acid-catalyzed racemization of (R)-1a and (S)-1b enantiomers with different acids in the selected solvents
a
entry
cmpd
acid (equiv)
solvent
temp (°C) time (h) (R)-1a/(S)-1b/4b (chiral HPLC, area %)
1
2
3
(S)-1b (98.6% ee) (1R)-CSA (1.13)
EtOH
EtOH
EtOH
78
78
78
60
60
80
28.9/68.5/2.4
28.8/68.7/2.3
37.1/58.9/3.8
39.7/57.5/2.8
5.3/94.5/0.28
38.3/61.7/ND
40.0/56.5/3.6
41.1/53.8/5.1
42.0/53.1/4.8
47.6/42.5/7.5
26.6/73.4/ND
42.1/57.9/ND
24.5/75.5/ND
20.7/79.3/ND
0.9/99.1/ND
0.8/99.2/ND
41.0/49.0/2.5
0.5/99.5f
(S)-1b
(S)-1b
(1S)-CSA (1.13)
(1R)-CSA (2.3)
1
50
4
5
6
7
8
9
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
TFA (2.3)
EtOH
EtOH
70
75
78
78
78
78
75
75
75
75
55
95
95
20
20
40
20
20
68
60
68
70
60
76
72
68
68
68
68
68
68
68
72
12
12, 66
12
12
48
e
e
3
MeSO H (4.0)
b
(1R)-CSA (1.0) + HCl (3.0) EtOH
(1R)-CSA (1.0) + HCl (4.0) EtOH
b
b
HCl (4.0)
EtOH
EtOH
EtOH
b
c
(R)-1a (99.8% ee) HCl (4.0)
1
0
(S)-1b
HCl (4.0)
c
HCl (20.0)
1
1
2
(S)-1b
(S)-1b
MeSO
3
H (4.0)
H
H
2
O:EtOH (1:1)
O:EtOH (1:1)
c
1
HCl (4.0)
2
c
HCl (20.0)
c
13
14
15
16
17
18
19
20
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
(S)-1b
HCl (4.0)
H
H
2
O
O
d
H
2
SO
4
(2.0)
2
BF
BF
3
·Et
2
O (1.0)
O (3.0)
CH
2
Cl
2
g
3
·Et
2
THF
0.5/99.5
h
i
MgBr
2
·Et
2
O (3.0)
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
7.5/92.5 , 9.0/91.0
SnCl
4
(3.0)
0.5/99.5j
k
TiCl
TiCl
4
(1.0)
(4.0)
3.5/96.5
THF
multiple productsl
4
a
The retention times of the byproducts 4b ) 8.1 min, (R)-1a ) 11.4 min, and (S)-1b ) 22.3 min as determined by chiral HPLC. A 1.0 M solution in EtOH. c A 37%
b
d
e
f
g
solution in H
2
O. A 96% solution. Not determined. Recovered 80% of (S)-1b plus the rest of uncharacterized byproducts. Recovered 93% of (S)-1b plus the rest of
h i
uncharacterized byproducts. Recovered 91% of (S)-1b plus the rest of uncharacterized byproducts. Recovered 61% of (S)-1b plus the rest of uncharacterized byproducts.
j
Recovered 95% of (S)-1b plus the rest of uncharacterized byproducts. k Recovered 91% of (S)-1b plus the rest of uncharacterized byproducts. The mixture was
l
uncharacterized.
Scheme 4. Proposed mechansism of acid-catalyzed racemization of (S)-enantiomer 1b
chronous elimination of an allylic proton from the 11-position
of 5 via path b would result in the olefin byproduct 4b.
chemical purity (>95%). When water was the solvent, 96%
SO (2 equiv) also produced a near racemic mixture of (R)-
a/(S)-1b (41.0%/49.0%) in 96% isolated yield with good
H
1
2
4
Conclusions
chemical purity (86.9%). Other Lewis acids displayed very weak
(or no) catalytical effect to racemize (S)-1b. A new and
economical process was developed for the reproducible recy-
cling of the undesired (S)-1b isomer, which could be a useful
method for the racemization of other enantiomerically pure
2,5,8-substituted 11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclo-
hepta-[1,2-a]naphthalene derivatives whenever it is needed.
The optically pure (R)-1a (99.8% ee) was unable to be
converted to the racemic mixture 1 using basic conditions; this
result was attributed to the absence of 2,8-phenolic protons on
the molecule. In contrast, when the optically pure (S)-1b (98.6%
ee) was treated with CSA in refluxing EtOH for 60-80 h, it
produced an (S)-1b enriched mixture (∼29%/69% to ∼37%/
59%; (R)-1a/(S)-1b). The addition of HCl to CSA further
increased the yield of (R)-1a to greater than 40% of the mixture.
The best reaction conditions were found with using HCl (4
equiv, 1.0 M in EtOH) to afford a near racemic mixture of (R)-
Experimental Section
The starting materials (R)-1a and (S)-1b were prepared in-
house, while the other reagents and solvents were obtained from
commercial suppliers and were used without further purification.
1a/(S)-1b (42.0%/53.1%) in 99% isolated yield with high
1
04
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development

1H NMR spectra were recorded at 300 MHz on a Bruker
Avance-300 instrument, and mass spectra were recorded on an
Agilent series 180 LC/MS instrument (positive/negative modes).
The chemical purity was determined on an Agilent series 1100
system at UVmax ) 254 and 340 nm, using a ZORBAX Eclipse
XDB-phenyl column (4.6 mm i.d. × 50 mm, 3.5 micron) at
purity of this material was confirmed by comparing the
analytical data of its H NMR, LC/MS, the retention times on
reverse phase HPLC (97%, area %) and chiral HPLC (>95%,
1
total area %) with that of an in-house prepared authentic
1
racemate 1. H NMR (300 MHz, CDCl
3
) δ 1.41 (m, 2 H), 1.58
(m, 4 H), 2.46 (m, 4 H), 2.71 (t, J ) 6.0, 2 H), 2.89 (t, J ) 5.8,
2 H), 3.73 (s, 3 H), 3.79 (s, 3 H), 4.03 (t, J ) 6.1, 2 H), 4.69
(t, J ) 5.5, 2 H), 6.06 (s, 1 H), 6.36 (d, J ) 1.0, 2 H), 6.48 (dd,
J ) 0.9, 8.3, 1 H), 6.58 (dd, J ) 0.9, 8.2, 1 H), 6.68 (d, J )
9.1, 2 H), 7.02 (d, J ) 8.4, 1 H), 7.17 (d, J ) 8.3, 1 H), 7.36
4
0 °C with flow rate of 1.0 mL/min and run time of 10.0 min.
Solvent system: A - 80% H
Gradient: B 20% f 80%/0.0 min f10.0 min, B 80% f 90%/
0.0 min f 11.0 min, B 90%/6.0 min, B 90% f 20%/17.0
min f 20.0 min. The retention times of the byproduct 4b is
.01 min and racemate 1 is 4.51 min. The optical purity/racemic
2 3
O + 0.1% TFA; B - 20% CH CN.
1
+
+
(d, J ) 9.0, 2 H). LC/MS m/z 514 (MH ), 536 (MNa ).
4
A Typical Acid-Catalyzed Racemization Procedure in
ratio of (R)-1a/(S)-1b were determined on an Agilent series 1100
system at UVmax ) 210 and 254 nm, using a Chiralpak AD
column (Chiral Technologies, Inc.) (4.6 mm ID × 250 mm,
2
H O for (S)-Enantiomer 1b. Into a four-neck 500 mL RBF
were charged (S)-1b (10.8 g, 0.021 mol, 93.2%) and water (250
mL). After the yellowish suspension was warmed to 60 °C, a
1
0 micron) at 20 °C with flow rate of 1.0 mL/min and run time
2 4
solution of 96% H SO (2.24 mL, 0.042 mol) was added
of 33.0 min with 100% 2-propanol as the mobile phase. The
retention time of the byproduct 4b is 8.1 min, (R)-1a is 11.4
min, and (S)-1b is 22.3 min. Preparative chiral HPLC separation
of (R)-1a/(S)-1b was conducted on a Chiralpak AD column
dropwise, and the formed yellow-orange suspension was heated
further to 95 °C (which became a clear, yellowish solution at
80 °C) and stirred for 68 h. After the reaction was cooled to 80
°C, toluene (100 mL) was added to the brownish mixture, and
then the pH was adjusted to ∼10 by addition of 50% aqueous
NaOH (4 mL) with intensive stirring. The resulting mixture
was cooled to 50 °C, diluted with THF (50 mL), and further
cooled to 20 °C with intensive stirring. The two phases were
then separated, and the organic layer was evaporated to afford
10.4 g (96.3% isolated yield; 87%, HPLC area %) of the near-
racemic 1 free base as a sticky, brown, foamy solid.
Chiral chromatographic purification of the above obtained
near-racemic 1 free base (8.0 g) afforded: 3.31 g (41% recovery
yield; 95.9%, RPHPLC, area %; 99.9% ee, chiral HPLC) of
the desired (R)-1a containing 1.55% (RPHPLC, area %) of 4b
and the rest of uncharacterized byproduct; plus 3.92 g (49%
recovery yield; 96.6%, RPHPLC, area %; 99.2% ee, chiral
HPLC) of the undesired (S)-1b, which also contained 0.95%
(RPHPLC, area %) of 4b.
(
5.0 cm i.d. × 150 mm, 10 µm), at 20 °C with flow rate of 50
mL/min and run time of 25.0 min, with 100% 2-propanol as
the mobile phase.
A Typical Acid-Catalyzed Racemization Procedure in
EtOH for (S)-Enantiomer 1b. A four-neck 500-mL round-
bottom flask (RBF) equipped with a thermocouple controller,
a mechanical stirrer, a condenser, a pressure-equalization drop-
ping funnel, a septum, and a nitrogen inlet adapter was charged
with (S)-1b (10.0 g, 0.0195 mol; 98.6% ee) and EtOH (120.0
mL, 190 proof), and the suspension was stirred under nitrogen.
A solution of HCl (77.8 mL, 0.0778 mol; 1.0 M in EtOH) was
added over a 10-min period (this addition was a mildly
exothermic process, the internal temperature was 28 °C after
the addition), and the reaction was heated to reflux (78 °C,
internal temperature) for 76 h. The progress of the racemization
was determined by chiral HPLC analysis (authentic racemate
1
(>99.5%) was used as a standard reference). After the reaction
Acknowledgment
time, the reaction was cooled to 20 °C, and the solvent was
concentrated at 60 °C under house vacuum (∼120 mmHg). The
resulting nearly racemic HCl salt was a dark-cherry, foamy
We are grateful to Dr. Michael Reuman, Sandra Beish, Scott
Youells, Zhiyong Hu, and Shawn Branum for helping in the
multihundred gram scale-up preparation of racemate 1 and to
2
solid, which was dissolved in D.I. H O (100 mL) and cooled
a
Dr. Wenju Wu for calculated pK values. We also greatly
to 0 °C in an ice-water bath, and the pH of the solution was
adjusted to g12.0 with 5 N NaOH solution (∼40 mL). The
alkaline solution was extracted with EtOAc (150 mL × 3), and
the combined organic phase was washed with brine (100 mL).
The solvent was concentrated at 60 °C under house vacuum to
afford 10.56 g (105.6% isolated yield) of the near-racemic 1
free base as a yellow-brown, foamy solid. The identity and
appreciate Dr. Julien Dingenen and Mr. Jeffery Proost for
technical support in chiral chromatographic separation of the
racemate 1.
Received for review July 12, 2008.
OP800237Y
Vol. 13, No. 1, 2009 / Organic Process Research & Development
•
105