Retrosynthetic Analysis of Nabumetone
John Stephenson, 410-1306. Chem 388: Organic Chemistry II. March 11, 2002
Introduction
Relafen is the trade name for a non-steroidal anti-inflammatory drug (NSAID)
generically known as Nabumetone. By the IUPAC naming conventions, it is chemically
designated to be 4-(6-methoxy-2-naphthalenyl)-2-butanone. (Rxlist.com, 2002)
Nabumetone has the ability to slow prostaglandin synthesis, a chemical used in the
peripheral nervous system to signal pain. Nabumetone works by inhibiting the activity of
cyclooxygenase, an enzyme that is critical in the biosynthesis of prostaglandin. Its action
is much like other NSAIDs in its class. Through the metabolism of Nabumetone in the
liver it functions as a pro-drug to its active metabolite, 6-methoxy-2-naphthylacetic acid.
To treat chronic pain, such as arthritis, typical dosage units are 500mg per tablet. The
starting dose is usually one 500mg tablet twice a day. (CPA, 1997)
Analysis
It is desired to find a suitable synthetic pathway to the target molecule, Nabumetone,
beginning with the starting material, 2-methoxynaphthalene, as shown in Scheme 1
O
?
CH3
O
O
CH3
CH3
Scheme 1: Nabumetone from starting material
Conducting a retrosynthetic analysis shows that there are four logical carbon-carbon
bonds that could be formed in order to produce the target molecule. Each of these four
breaks produce two pairs of synthons. The normal synthons with standard latent polarity
are shown on the left in the following schemes. The so-called umpoled synthons with
reversed latent polarity are shown on the right. Certain combinations, notably the
Grignard reactions that produce secondary alcohols, will require oxidation to the
corresponding ketone to arrive at the desired product.
Starting with the bond between the ring and the side chain, we are given two pairs of
synthons as shown in Scheme 2. The synthetic equivalent to the aromatic anion could be
a Gilman reagent. The synthetic equivalent to the cation ion is a conjugated ketone. Since
Grignards are likely to react at the carbonyl group, Gilman reagents are preferred. It
should be pointed out that Gilman reagents are not the only choice of carbon
nucleophiles, the Grignard reaction of 3-buten-2-one with 6-methoxy-2naphthylmagnesium bromide has been shown to produce Nabumetone in satisfactory
yields. (Chen, 1989) A synthetic equivalent to a carbon nucleophile beta to the carbonyl
was not found.
O
C
H2C
+
C
+
CH3
O
O
+
H2C
+
CH3
O
CH3
CH3
O
CuLi
Br
C
CH3
O
O
CH3
CH3
?
2
Scheme 2: Synthons from first break of Nabumetone
Moving to the right, it is possible to form the neighbouring carbon-carbon bond that is
situated between the carbon atoms alpha and beta to the carbonyl group of Nabumetone
as shown in Scheme 3. The normal synthetic equivalents would be the naphthalene
equivalent of benzyl bromide reacting with acetone enolate. The umpoled synthetic
equivalents would be to standard Grignard/epoxide chemistry.
CH2
+
+
CH3
H2C
H2C
+
CH3
O
O
CH3
CH3
CH2Br
O
O
CH2
O
+
H3C
CH2MgBr
O
CH3
CH3
O
O
CH3
Scheme 3: Synthons from second break of Nabumetone
Moving one carbon bond toward the carbonyl group, it is possible to form the bond
between the carbonyl and the carbon alpha to the carbonyl group using two sets of
synthons and possible synthetic equivalents as in seen in Scheme 4. On the left, the
CH3
normal equivalents are standard Grignard chemistry. On the right a thioketal is chosen as
a compound that will produce the dithiane anion, functionally equivalent to the acyl anion
synthon shown.
+
O
CH2
O
+
C
+
CH3
CH3
O
H
C
+
C
CH3
CH3
CH2MgBr O
O
O
CH2
CH2Br
CH3
CH3
O
CH3
Scheme 4: Synthons from third break of Nabumetone
As a final possibility the carbon-carbon bond between the methyl and the carbonyl group
could be formed using the synthons and possible synthetic equivalents in Scheme 5. The
normal synthons produce a pair suitable for standard Grignard chemistry, and on the right
the thioketal equivalent are chosen.
S
S
H
CH3
O
O
C
+
C
+
CH3
+
+
CH3
O
O
CH3
CH3
O
C
S
H
S
H
CH3MgBr
O
O
CH3
CH3
Scheme 5: Synthons from fourth break of Nabumetone
Finally we need to select a suitable synthetic pathway. With the desire to reduce the
number of steps, both carbon-carbon bond forming steps and functional group
interconversions, the choice is made to use the synthetic equivalents to the normal
synthons shown in Scheme 2.
First we need to convert our starting material to 2-methoxy-6-bromonaphthalene. Since
the starting material has an activating ortho- and para- directing methoxy group,
bromination will be expected to occur in both places. Luckily this problem has solved by
brominating both positions and then selectively debrominating the ortho- group with iron
powder (Borsotti, 1986). From there, the aryl lithium compound is prepared, then the
Gilman reagent is made which can react with methyl vinyl ketone to produce the target
molecule as shown in Scheme 6. The cost of all the reagents is summed up in Table 1.
CH3Br
Br
Br2
Fe
2 Li
Li
pentane
+
O
O
O
CH3
CH3
CH3
LiBr
CuI
ether
O
CH3
ether
H3O+
O
C
O
+
O
CH3
CH3
CuLi
2
Scheme 6: Proposed synthesis of Nabumetone
Table 1: Cost of reagents (ChemACX.com, 2002)
Chemical
2-methoxynaphthalene
Bromine
Iron powder
Dry granular lithium
Copper (I) iodide
3-buten-2-one
Supplier
Alfa Aesar
Lancaster Synthesis Inc.
Acros Organics - USA
Acros Organics - USA
H&S Chemical Co. Inc.
Acros Organics – USA
Price ($US)
$54.78 / 1 kg
$166.43 / 3.5 kg
$86.57 / 2 kg
$236.72 / 250g
$86.81 / 1 kg
$106.15 / 1L
References
Borsotti, Giampiero. 1986. “Synthesis of 2-methoxy-6-bromonaphthalene”.
Eur. Pat. Appl, 8 pp.
Cambridge Soft. 2002. http://www.chemacx.com/, 2002.
Canadian Pharmaceutical Association. 1997. “CPS: Compendium of Pharmaceuticals and
Specialties” p1348-1349
Chen, Zuxing; Wang, Shiming. 1989. “Novel synthesis of Nabumetone” Dep. Chem.,
Hubei Univ., Wuhan, Peop. Rep. China. Zhongguo Yiyao Gongye Zazhi
(1989), 20(4), 145-6.
Rxlist.com. 2002. “Nabumetone – Rxlist monographs”
http://www.rxlist.com/cgi/generic/nabume.htm