[14C]dimethyltitanocene and [14C] methyl(methyltrimethylsilyl) titanocene - Reagents for the [14C] olefination of carbonyl compounds: Synthesis of [14C]aprepitant

Article abstract of DOI:10.1002/jlcr.1667

A neurokinin (NK-1) receptor antagonist, [¹⁴C]Aprepitant, was synthesized using two labeled olefination reagents: [¹⁴C] dimethyltitanocene 1 and [¹⁴C]methyl (methyltrimethylsilyl)titanocene 7. Both reagents can be readily

Full text of DOI:10.1002/jlcr.1667

Note
Received 1 May 2009,
Revised 17 June 2009,
Accepted 1 July 2009
Published online 11 August 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1667
[14C]Dimethyltitanocene and
[14C]Methyl(methyltrimethylsilyl) titanocene –
Reagents for the [14C]olefination of carbonyl
compounds: synthesis of [14C]Aprepitant
Ã
M. A. Wallace, D. C. Dean, and D. G. Melillo
A neurokinin (NK-1) receptor antagonist, [14C]Aprepitant, was synthesized using two labeled olefination reagents:
[
[
14C]dimethyltitanocene 1 and [14C]methyl (methyltrimethylsilyl)titanocene 7. Both reagents can be readily prepared from
14C]methyllithium and have been shown to convert a variety of carbonyls to [14C]methylenes in good radiochemical yields.
Keywords: [14C]dimethyltitanocene; [14C]methyl(methyltrimethylsilyl)titanocene; olefination; NK-1; organometallic
formation of the lithiate and addition to dichlorotitanocene,
Introduction
produced a viable reagent (specific activity ꢀ10.7 mCi/mmol),
which could be used without further purification. With the
labeled reagent in hand, [14C]olefination of highly functionalized
ester 2 proceeded using 3 equivalents of 1 at 851C in toluene
over 16 h to afford [14C]vinyl ether 3 in an isolated overall 30%
radiochemical yield. Although the chemical conversion from
ester to the labeled vinyl ether is quite clean, radiochemical
detection reveals the formation of highly polar titanium-oxide
byproducts, which Petasis hypothesizes quenches unreacted
[14C]dimethyltitanocene.5 This results in the need for three
equivalents of 1 to achieve good conversion to [14C]vinyl ether
3. Hydrogenation of the vinyl ether 3 with Pd/C afforded a 9:1
mixture of diastereomers. Removal of the benzyl protecting
group by hydrogenation in the presence of camphorsulfonic
acid affored 4 as the camphorsulfonic acid salt in 85% yield. The
triazole ring was formed by treatment of 4 with chloroami-
drazone over potassium carbonate, then, following workup, the
crude mixture was heated to reflux in xylene, to give crude 5.
Preparative chromatography afforded pure carbon-14-labeled
apprepitant 5, which was used in carry out ADME studies.
While [14C]dimethyltitanocene provided a viable synthetic
route to the target tracer, the breakdown of [14C]dimethyltita-
nocene to the postulated reactive carbene intermediate6 results
in the loss of [14C]methane7, intrinsically reducing the overall
yield to a maximum of 50%.6 To address this issue, we had
hoped that generation of a mixed titanocene could increase
the overall yield based on [14C]methyl iodide. Petasis has
shown that several types of alkyl groups, including benzyl,8
Potential clinical applications of a substance P inhibitor include
treatment for pain, depression, and chemotherapy-induced
nausea and vomiting, for which Aprepitant was approved.1
While several syntheses have been previously described,2 we
envisioned that installing the label in the methyl position would
allow for accurate determination of the metabolic fate of
Apprepitant, via ADME studies, with minimal loss of label
(Scheme 1). Although several titanium based reagents could be
useful to perform this transformation (i.e. Tebbe3 or Grubbs4
reagents), their difficult preparation has excluded them as
practical methods to introduce a carbon-14 label. Petasis has
shown that dimethyltitanocene, conveniently generated from
dichlorotitanocene and methyllithium, can be used to convert a
variety of carbonyl compounds to methylenes.5 Requests for a
tracer labeled in a methyl group along with the availability of
intermediates prompted our investigation into utilizing carbon-
14-labeled dimethyltitanocene, as a method to introduce the
labeled methylene, as shown in Scheme 1.
Results and discussion
The synthesis of [14C]dimethyltitanocene (1) was accomplished
by addition of 2.3 equivalents of [14C]methyllithium, freshly
prepared from [14C]methyl iodide and t-butyl lithium to
commercially available dichlorotitanocene. The stability and
reactivity of the resulting [14C]dimethyltitanocene (1) was
dependent on the reagents specific activity. Attempts to convert
carbonyls to carbon-14-labeled olefins using [14C]dimethyltita-
nocene with a specific activity greater than 40 mCi/mmol
resulted in poor yields (ꢀ2%); presumably due to rapid
radiolytic decomposition of the reagent. Attempts to purify
the reagent by recrystallization from hexane, also led to
decomposition. Further investigation found that dilution of
the [14C]methyl iodide with unlabeled carrier, followed by
Department of Drug Metabolism, Merck Research Laboratories, 126 Lincoln Ave.,
P.O. Box 2000, Rahway, NJ 07065, USA
*Correspondence to: M. A. Wallace, RY80R-104, P.O. Box 2000, Rahway, NJ
07065, USA.
E-mail: mike_wallace@merck.com
J. Label Compd. Radiopharm 2009, 52 514–517
Copyright r 2009 John Wiley & Sons, Ltd.

M. A. Wallace et al.
t-BuLi
Cp2TiCl2
*
14C]CH3I
[
14C]CH3Li
Cp2Ti(CH3)2
[
ether
1
CF3
CF3
O
*
Cp2Ti(*CH3)2, toluene
1. H2, (40 psi), Pd/C, EtOH, EtOAc
2. Camphorsulfonic acid, H2, Pd/C
CF3
CF3
O
O
O
N
O
N
Ph
F
Ph
F
2
3
CF3
CF3
NHCO2CH3
NH2
*
N
*
CF3
CF3
ClH2C
O
O
O
O
K2CO3, DMF
N
2. xylenes, reflux
3. HPLC purification
N
H
H
N
F
O
F
N
N
H
4
5
Scheme 1.
[
14C]CH3Li
Cp
(CH3)3SiCH2MgCl
THF, ether
Cp
Ti
Cp
Si(CH3)3
Ti
Cp2TiCl2
Si(CH3)3
Cp
CH3
Cl
*
6
7
Scheme 2.
cyclopropyl,9 and methyltrimethylsilyl10,11 will react with carbo-
nyls to afford benzylidenes, cyclopropenes, and vinylsilanes,
respectively. The different reaction conditions for each complex
suggests that alkyl transfer rates could be manipulated
through control of the reaction conditions. Petasis also has
described the sequential addition of organometallics to
dichlorotitanocene.12 Based on this methodology, we have
developed a novel mixed reagent, [14C]methyl(methyltrimethyl-
silyl)titanocene (7) as shown in Scheme 2. Treatment of
dichlorotitanocene with methyltrimethylsilyl magnesium chlor-
ide at À601C afforded chloro(methyltrimethylsilyl)titanocene 6
in 90% isolated yield. This stable intermediate was then treated
with 1.1 equivalents of [14C]methyllithium to afford the desired
[14C]methyl(methyltrimethylsilyl)titanocene 7 in 50% isolated
radiochemical yield.
Experimental
Radioactivity measurments were carried out using Packard Tri-
carb 1000 TR liquid scintillation spectrometer with Scintiverse
1TM as scintillation medium. Analytical HPLC analyses were
performed using a Dupont Zorbax RX C-8 (4.6 mm  25 cm),
Rainin UV-1 detector at 254 nm, Radiomatic radioactivity
monitor, Spectra-Physics SP8810 LC pump and controller, and
software run on an IBM PS/2 computer. Preparative HPLC were
carried out using Altex pumps with a Beckman UV detector at
254 nm and either a Whatman M20 (22.1 mm  25 cm) Partisil or
Dupont (22.1 mm  25 cm) Zorbax RX C-8 column. The identities
of appropriate labeled intermediates as well as the final product
were established by co-elution via HPLC with authentic material.
Investigation of the ability of 7 to convert esters, ketones, and
aldehydes to [14C]methylenes found that when 7 is heated to
[
14C]Dimethyltitanocene (1)
1401C in xylenes in the presence of carbonyl compounds, both [14C]methyl iodide (25 mCi, 0.454 mmol) was transferred by
[14C]methylenes and the corresponding unlabeled vinylsilanes vacuum line to 2 mL of ether containing 64 mg (0.454 mmol)
were detected. Similar to Petasis’ bis and tris silyl-titanium unlabeled methyl iodide. The ethereal mixture was warmed to
complexes, the generation of titanium-oxide byproducts was À781C, t-butyl lithium (1.7 M, 575 mL) was added dropwise, and
suppressed,9 resulting in much cleaner radiochemical conver- the mixture aged at À781C for 30 min. Dichlorotitanocene
sions. Good radiochemical yields could be obtained using 2 (112 mg, 0.454 mmol) was slurried into ether (4 mL) and cooled
equivalents of 7. Yields for representative carbonyl compounds to 01C. The [14C]methyllithium was transferred by cannula, and
are summarized in Table 1.
the mixture aged for 30 min at 01C. Unlabeled methyllithium
J. Label Compd. Radiopharm 2009, 52 514–517
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

M. A. Wallace et al.
Table 1. Carbon-14 olefinations with [14C]Methyl(methyltrimethylsilyl)titanocene
SI(CH3)3
O
*
7 (2 equivalents)
toluene
51%
33%(30%)
Si(CH3)3
O
*
H
7 (2 equivalents)
H
H
toluene
25%(25%)
39%
CF3
CF3
*
O
CF3
CF3
7 (2 equivalents)
O
O
O
O
toluene
N
N
Bn
Bn
F
F
42% (25%)
* overall radiochemical assay yields shown in ( ).
(1.6 M, 50 mL) was added until the yellow color persisted. The The titanocene was redissolved in toluene (7.764mCi, specific
mixture was aged an additional 15 min and quenched with activity 18.2mCi/mmol) and could be used without further
water (5 mL). The mixture was diluted with ether (10 mL) and the purification.
layers separated. The organic phase was washed with water
(5 mL), brine (5 mL), dried over MgSO4, filtered, and concen-
Methylenation of ester 2 with [14C]dimethyltitanocene:
trated to afford 98 mg (9.5 mCi, 10.7 mCi/mmol) of [14C]di- Synthesis of Apprepitant
methyltitanocene. The [14C]dimethyltitanocene was redissolved
in toluene and used as a stock solution (14% w/w) without the
need for further purification.13
Ester 2 (10.5 mg, 0.08 mmol) was dissolved in 800 mL of toluene
and 350 mL of THF and [14C]dimethyltitanocene (50 mg,
0.24 mmol, 3 equivalents, 4.5 mCi) was added. The mixture was
aged at 861C for 18 h. HPLC (Zorbax RX-C8, 65A/35B, A = CH3CN,
B = 0.1% H3PO4) indicated complete consumption of ester (25%
[
14C]methyl(methyltrimethylsilyl)titanocene (7)
Monochloro(trimethylsilyl methyltitanocene) was generated as radiochemical yield). Liquid scintillation counting of the reaction
described by Petasis.4 [14C]methyl iodide (25 mCi, 0.454 mmol) mixture indicated 2.2 mCi remained. The reaction mixture was
was transferred by vacuum line into 2 mL of ether. The ether was concentrated and the residue redissolved in methanol/water.
warmed to À781C and t-butyl lithium (1.7M, 275 mL) was added The mixture was filtered, to remove titanocene-oxide bypro-
dropwise. The mixture was aged for 30min at À781C. The ducts, and concentrated. The crude residue was purified by silica
monochlorotitanocene 6 (139mg, 0.454 mmol) was dissolved in gel chromatography (hexanes) to afford [14C]vinyl ether 3
6 ml of ether and cooled to 01C. The [14C]methyl lithium was (500 mCi, spec. act. 16 mCi/mg, 12% radiochemical yield). The
transferred by cannula and the flask rinsed with ether (1 mL). The [14C]vinylether 3 was dissolved in methanol and 15%, by weight,
mixture was aged for 30min at room temperature (reddish to of Pd/C (10%) was added. The mixture was stirred under 40 psi
orange color) and then unlabeled methyllithium (300mL, 1.0 M) H2 for 4 h upon which HPLC showed [14C]vinyl ether 3 was
was added dropwise. The mixture was aged an additional 15min consumed. R-Camphorsulfonic acid (1.1 equivalents) was added
at 01C (orange to yellow color) and then quenched with water and the mixture aged under 40 psi of H2 for 16 h. The mixture
(5mL). The mixture was diluted with ether (10 mL) and the layers was filtered and concentrated. The amine 4 (35 mg, 0.06 mmol)
separated. The organic phase was washed with water (5mL), was treated with chloroamidrazone (12 mg, 0.064 mmol, 1.2
brine (5mL), dried over MgSO4, filtered, and concentrated to equivalents) over potassium carbonate (17 mg, 0.12 mmol, 2
afford 119 mg of [14C]methyl-methyltrimethylsilyltitanocene (7). equivalents) in DMF (1 mL). The reaction mixture was diluted
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 514–517

M. A. Wallace et al.
with water (20 mL) and extracted with ethyl acetate (3 Â 10 mL). products can be achieved with 2 equivalents of 7, as opposed to
The organic phase was dried and concentrated and the resulting 3 equivalents needed with reagent 1. Lastly, although 5 may
oil was dissolved in xylenes (2 mL) and the mixture refluxed for generate significant amounts of undesired vinyl silanes, their
6 h. Following concentration, the crude tracer was purified by non-polar nature generally make them separable from the
preparative HPLC (Zorbax RX C8, 40A/60B, A = CH3CN, B = 0.1% desired carbon-labeled methylene products. Also, 7 provides
H3PO4). Isolation by extraction, followed by recrystallization access to potentially higher specific activity tracers as the
from methanol/water 2/1 (3 mL), afforded 200 mCi (4% from reagents oxidation/decomposition was not observed. Further
[14C]methyl iodide) of 98.7% radiochemically pure apprepitant 5. experiments are underway using different complexes in an
attempt to influence the reaction pathway to favor olefination
Olefination of ester 2 with [14C]methyl-methyltrimethylsi- and further increase overall label incorporation.
lyltitanocene (7)
Ester 2 (10.5 mg, 0.019 mmol) was dissolved in 300 mL of xylenes
and [14C]methyl (methyltrimethylsilyl)titanocene (7) (16 mg,
0.057 mmol, 3 equivalents, 1.2 mCi) was added. The mixture
References
was aged at 1501C for 4 h. HPLC analysis (Zorbax RX C8, 65A/
[1] R. M. Navari, R. R. Reinhardt, R. J. Gralla, M. G. Kris, P. J. Hesketh,
35B, A = CH3CN, B = 0.1% H3PO4) showed the mixture contained
A. Khojasteh, H. Kindler, T. H. Grote, K. Pendergrass,
S. M. Grunberg, A. D. Carides, B. J. Gertz, N. Engl. J. Med. 1999,
starting ester (2%), [14C]methylene product (42% (19% radio-
chemical yield)), and vinyl silane product (55%). Liquid scintilla-
tion counting of the reaction mixture indicated 390 mCi of the
desired [14C]vinyl ether that had a radiochemical purity of 60%.
340, 190–195. M. S. Kramer, N. Cutler, J. Feighner, R. Shrivastava,
J. Carman, J. J. Sramek, S. A. Reines, G. Liu, D. Snavely, E. Wyatt-
Knowles, J. J. Hale, S. G. Mills, M. MacCoss, C. J. Swain, T. Harrison,
R. G. Hill, F. Hefti, E. M. Scolnick, M. A. Cascieri, G. G. Chicchi,
S. Sadowski, A. R. Williams, L. Hewson, D. Smith, E. J. Carlson,
R. J. Hargreaves, N. M. J. Rupniak, Science 1998, 281, 1640–1645.
[2] K. M. J. Brands, S. W. Krska, T. Rosner, K. M. Conrad, E. G. Corley,
M. Kaba, R. D. Larsen, R. A. Reamer, Y. Sun, F. R. Tsay, Org. Process
Res. Dev. 2006; 10: 109–117. M. Journet, D. Cai, D. L. Hughes,
J. J. Kowal, R. D. Larsen, P. J. Reider, Org. Process Res. Dev. 2005, 9,
490–498. K. M. J. Brands, J. F. Payack, J. D. Rosen, T. D. Nelson,
A. Candelario, M. A. Huffman, M. M. Zhao, J. Li, B. Craig, Z. J. Song,
D. M. Tschaen, K. Hansen, P. N. Devine, P. J. Pye, K. Rossen,
P. G. Dormer, R. A. Reamer, C. J. Welch, D. J. Mathre, N. N. Tsou,
J. M. McNamara, P. J. Reider, J. Am. Chem. Soc. 2003, 125,
2129–2135. C. C. Cowden, R. D. Wilson, B. C. Bishop, I. F. Cottrell, A.
J. Davies, U. H. Dolling, Tetrahedron Lett. 2000, 8661–8664.
C. S. Elmore, D. C. Dean, Y. Zhang, D. G. Melillo, J. Label. Compd.
Radiopharm. 2004, 47, 837–846. J. J. Hale, S. G. Mills, M. MacCoss,
P. E. Finke, M. A. Cascieri, S. Sadowski, E. Ber, G. G. Chicchi, M. Kertz,
J. Metzger, G. Eiermann, N. N. Tsou, F. D. Tattersall, N. M. J. Rupniak,
A. R. Williams, W. Rycroft, R. Hargreaves, D. E. MacIntyre, J. Med.
Chem. 1998, 41, 4607–4614. J. F. Payack, M. A. Huffman, D. Cai,
D. L. Hughes, P. C. Collins, B. K. Johnson, I. F. Cottrell, L. D. Tuma,
Org. Process Res. Dev. 2004, 8, 256–259.
[3] F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978; 100;
3611–3613. S. H. Pine, Org. React. (NY) 1993, 43, 1–91 (review).
[4] T. R. Howard, J. B. Lee, R. H. Grubbs, J. Am. Chem. Soc. 1980, 102,
6876–6878. K. C. Ott, R. H. Grubbs, J. Am. Chem. Soc. 1981, 103,
5922–5923. D. Strauss, R. H. Grubbs, Organometallics 1982, 1,
1658–1661. E. V. Anslyn, R. H. Grubbs, J. Am. Chem. Soc. 1987, 109,
4880–4890.
[5] N. A. Petasis, E. I. Bzowej. J. Am. Chem. Soc. 1990, 112, 6392–6394.
N. A. Petasis, S. P. Lu, Tetrahedron Lett. 1995, 36, 2393–2396.
N. A. Petasis, E. I. Bzowej. U.S. Patent No. 5,087,790, Feb. 11, 1992.
N. A. Petasis, Y.-H. Hu, Tetrahedron Lett. 1995, 36, 6001–6004.
N. A. Petasis, M. A. Patane, Tetrahdron Lett. 1990, 31, 6799.
[6] D. L. Hughes, J. F. Payack, D. Cai, T. R. Verhoeven, P. J. Reider,
Organometallics 1996, 15, 663–667.
Olefination of Dibenzosurbenone with 7
Dibenzosurbenone (5.9 mg, 0.028 mmol) was dissolved in 300 mL
of xylenes. [14C]methyl(methyltrimethylsilyl)titanocene 7 (stock
solution toluene, 15.8 mg, 0.056 mmol, 2 equivalents, 1.2 mCi)
was added and the mixture aged at 1501C for 4 h. HPLC analysis
(Zorbax RX C8, 50A/50B, A = CH3CN, B = 0.1 % H3PO4) showed
the reaction mixture contained starting dibenzosurbenone
(15%), [14C]methylene product (33% (30% radiochemical yield.)),
and vinyl silane product (51%). A count of reaction mixture
indicated 400 mCi (33%) remained of which 95% was the desired
[14C]methylene compound.
Olefination of 2-Napthaldehyde with 7
2-Napthaldehyde (1.0 mg, 0.0064 mmol) was dissolved in 300 mL
of xylenes. [14C]methyl-methyltrimethylsilyltitanocene 7 (stock
solution toluene, 11.9 mg, 0.013 mmol, 2 equivalents, 225 mCi)
was added and the mixture aged at 1501C for 2 h. (prolonged
heating results in several radiochemical impurities). HPLC
analysis (Zorbax RX C8, 50A/50B, A = CH3CN, B = 0.1 % H3PO4)
showed the mixture contained starting aldehyde (38%),
[14C]methylene product (22% (25% radiochemical yield.)), and
vinyl silane product (39%). A count of reaction mixture indicated
75 mCi (33%) remained of which 90% was the desired
[14C]methylene product.
Conclusion
As our investigation into titanium mediated [14C]olefinations
continues, we have shown that both [14C]dimethyltitanocene (1)
and [14C]methyl(methyltrimethylsilyl) titanocene (7) can be
readily prepared and are quite capable of converting carbonyls
to [14C]methylenes in reasonable radiochemical yields. Although
1 provides usable radiochemical yields in many instances, 7
does offer several advantages: Most importantly, generation
of the mixed titanocene 7 requires only one equivalent
of [14C]methyllithium, reducing the necessary amount of
[14C]methyl iodide. Good radiochemical yields of [14C]olefination
[7] As labeled methane is generated during the reaction, periodic
venting should be used to prevent pressure buildup, especially on
large scale.
[8] N. A. Petasis, E. I. Bzowej, J. Org. Chem. 1992, 57, 1327–1330.
[9] N. A. Petasis, E. I. Bzowej, Tetrahedron Lett. 1993, 34, 943–946.
[10] N. A. Petasis, I. Akritopoulou, Synlett 1992, 665–667.
[11] N. A. Petasis, J. P. Staszzewski, D.-K. Fu, Tetrahedron Lett. 1995, 36,
3619–3622.
[12] N. A. Petasis, D.-K. Fu, J. Am. Chem. Soc. 1993, 115, 7208–7214.
[13] Dimethyltitanocene will decompose if stored in solid form.
Dimethyltitanocene kept in toluene solution is stable for several
months.
J. Label Compd. Radiopharm 2009, 52 514–517
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org