Asymmetric synthesis of an MMP-3 inhibitor incorporating a 2-alkyl succinate motif

Article abstract of DOI:10.1021/op034001y

An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the

Full text of DOI:10.1021/op034001y

Organic Process Research & Development 2003, 7, 362−368
Asymmetric Synthesis of an MMP-3 Inhibitor Incorporating a 2-Alkyl
Succinate Motif
Christopher P. Ashcroft, Stephen Challenger, Andrew M. Derrick, Richard Storey, and Nicholas M. Thomson*
Department of Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment, Ramsgate Road,
Sandwich, Kent CT13 9NJ, United Kingdom
Abstract:
An efficient and practical synthesis is presented of the phar-
maceutically active MMP-3 inhibitor UK-370,106 (1) via an
olefination/catalytic asymmetric hydrogenation sequence. Com-
mercially available 5-bromo-2-iodotoluene was converted in two
steps to the biarylpropanal equivalent (11), which was reacted
with the phosphonosuccinate (10) to selectively afford the trans-
â-substituted itaconate (12). Catalytic asymmetric hydrogena-
tion of the itaconate (12) was achieved in good conversion and
with 86-96% enantiomeric excess with a range of phosphine-
modified rhodium and ruthenium cationic complexes. The
resulting enantiomerically enriched 2-alkyl succinate (2) was
elaborated to the desired drug substance (1) in two steps. The
synthesis benefits from several crystalline intermediates, al-
lowing control of process impurities, and can be operated safely
within parameters readily achievable on scale. Investigations
into the polymorphic forms of (1) have shown that the
medicinal chemistry route, as outlined in Scheme 1. The
compound crystallizes in planar sheets, based on a backbone
dipeptide (3) was prepared from the coupling of BOC (S)-
of hydrogen-bonding amide and acid functionalities, with large
tert-leucine3 with (S)-O-methyl-phenylglycinol,4 followed by
hydrophobic pockets formed by the biarylpropyl groups. An
deprotection to the free amine. Assembly of the chiral
understanding of this crystal-packing arrangement has aided
succinate (2) began with a selective Suzuki coupling of
the development of crystallization processes allowing complete
5-bromo-2-iodotoluene with phenylboronic acid to afford the
control over solid form.
biaryl bromide (4).5 Formation of the Grignard reagent and
subsequent addition to glutaric anhydride gave the keto acid
(5), which was reduced to the biarylpentanoic acid (6).
Conversion of the acid (6) to the acyl oxazolidinone (7)
allowed installation of the key chiral succinate stereocenter
via an asymmetric alkylation utilizing Evans’ methodology.6
Thus, treatment of the acyl oxazolidinone (7) with sodium
bis(trimethylsilyl)amide, followed by addition of tert-butyl
bromoacetate, afforded the 2-alkyl succinate derivative (8)
with >98% diastereomeric excess. Cleavage of the chiral
auxiliary afforded the mono-protected succinate (2) in good
overall yield. The succinate (2) was then coupled with the
dipeptide (3) and subsequently deprotected under acidic
conditions to afford the desired product (1). Approximately
1 kg of UK-370,106 (1) was prepared in this manner.
Introduction
Matrix metalloproteases (MMPs) are involved in the
repair, degradation, and remodeling of extracellular matrix
proteins. Since they have a destructive potential, failure to
regulate MMP activity in physiological processes may
underlie a number of pathological conditions, such as tissue
destruction, as in venous and diabetic ulcers.1 UK-370,106
(1), a potent and selective MMP-3 inhibitor discovered by
chemists at Pfizer,2 has been progressed into development
as a candidate designed to treat pathological conditions
involving tissue destruction. Retrosynthetic disconnection of
(1) leads to a suitably protected key chiral 2-alkyl succinate
building block (2) and the dipeptide (3). Initial quantities of
(1) were prepared via these intermediates utilizing a modified
(3) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2000, 39, 2752.
(4) Alezra, V.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H. P.
Tetrahedron Lett. 2000, 41, 1737.
(5) Compound (4) has previously been prepared by a Gomberg-Bachmann-
Hey reaction (4-bromo-2-methylaniline, isoamyl nitrite, benzene, reflux):
Gomberg, M.; Pernet, J. C. J. Am. Chem. Soc. 1926, 48, 1372 and from the
coupling of phenyldiazonium tetrafluoroborate with an arlylboronic ester:
Willis, D. M.; Strongin, R. M. Tetrahedron Lett. 2000, 41, 6271.
(6) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104,
1737. (b) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
* To whom correspondence should be addressed. E-mail: Nick_Thomson@
sandwich.pfizer.com.
(1) Zask, A.; Levin, J. I.; Killar, L. M.; Skotnicki, J. S. Curr. Pharm. Des.
1996, 2, 624.
(2) (a) Fray, M. J.; Dickinson, R. P.; Dack, K. N. PCT Int. Pat. Appl. WO99/
35124, 1999. (b) Fray, M. J.; Dickinson, R. P.; Huggins, J. P.; Occleston,
N. L. J. Med. Chem. 2003, 46.
362
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development
10.1021/op034001y CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/22/2003

Scheme 1. Medicinal Chemistry route to UK-370,106 (1)a
Scheme 2. Stobbe route to â-substituted itaconate
derivatives and chiral 2-alkyl succinates
substance (1) in good overall yield and with an appropriate
purity profile.
Results and Discussion
A number of methods are known in the literature for the
construction of enantiomerically pure 2-alkyl succinates.7-9
The most appealing in terms of practicality and efficiency
are those involving the asymmetric catalytic hydrogenation
of â-substituted itaconate derivatives.8 Of particular interest
to us was the method described by Burk et al., involving
the Stobbe condensation of an aldehyde or ketone with a
dialkyl succinate, followed by asymmetric hydrogenation of
the resulting itaconate products, catalyzed by a cationic
rhodium complex in concert with a chiral diphosphine
ligand.9 Whilst this method affords rapid access to 2-alkyl
succinates in good enantiomeric excess, further manipulation
is required to afford succinates with an appropriate protect-
ing-group alignment for our synthesis of (1) (Scheme 2).
Our attention was therefore turned to the development of an
olefination/asymmetric hydrogenation approach leading di-
rectly to the monoprotected succinate (2) without further
manipulation of protecting groups.10
Towards this goal, the biaryl bromide (4) (Scheme 3) was
reacted with allyl alcohol under Jeffery’s conditions11 to
afford a biarylpropanal, which was conveniently isolated in
a solid form as the sodium metabisulfite adduct (11).
Concomitantly, we found that the phosphonosuccinate (10)
could be readily prepared from triethyl phosphonoacetate and
isolated as a crystalline solid. Treatment of the hydroxy
sulfonate (11) and the phosphorus reagent (10) with an excess
a Conditions: (i) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide‚HCl, HOBT,
NMM, CH2Cl2, rt; HCl, CH2Cl2, rt, 79%; (ii) PhB(OH)2, Na2CO3, Pd(OAc)2,
PPh3, acetone, H2O, reflux, 80%; (iii) Mg, glutaric anhydride, THF, -40 °C,
73%; (iv) Et3SiH, TFA, rt, 86%; (v) (COCl)2, CH2Cl2, rt; (S)-4-benzyl-2-
n
oxazolidinone, BuLi, THF, -78 °C, 89%; (vi) NaHMDS, tert-butyl bromoac-
(7) (a) Hirayama, R.; Yamamoto, M.; Tsukida, T.; Matsuo, K.; Obata, Y.;
Sakamoto, F.; Ikeda, S. Bioorg. Med. Chem. 1997, 5, 765. (b) Broadhurst,
M. J.; Brown, P. A.; Lawton, G.; Ballantyne, N.; Borkakoti, N.; Bottomley,
K. M. K.; Cooper, M. I.; Eatherton, A. J.; Kilford, I. R.; Malsher, P. J.;
Nixon, J. S.; Lewis, E. J.; Sutton, B. M.; Johnson, W. H. Bioorg. Med.
Chem. Lett. 1997, 7, 2299. (c) Chevtchouk, T.; Ollivier, J.; Salaun, J.; Merlet,
D.; Courtieu, J. Tetrahedron Asymmetry 1997, 8, 999.
(8) (a) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333. (b) Talley, J. J.
U.S. Patent 4,939,288, 1990. (c) Berens, U.; Burk, M. J.; Gerlach, A.; Hems,
W. Angew. Chem., Int. Ed. 2000, 39, 1981. (d) Jendralla, H. Synthesis 1994,
5, 494.
etate, THF, -78 °C, 65%; (vii) LiOH, H2O2, THF, H2O, 0 °C, 85%; (viii) 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide‚HCl, (3), HOBT, iPr2NEt, CH2Cl2,
rt, 96%; (ix) TFA, CH2Cl2, rt, 59%
Opportunities to scale this chemistry further were limited
by the lack of crystalline intermediates in the synthesis,
leading to a lack of purification points and therefore
inadequate control of the impurity burden. The route also
suffered from two undesirable cryogenic reactions, the use
of an expensive stoichiometric chiral auxiliary and safety
concerns regarding the use of peroxide to cleave the chiral
auxiliary. Key to the success of the clinical program, was
the development of a scalable and cost-effective asymmetric
synthesis of the 2-alkyl succinate (2), leading to drug
(9) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew. Chem.,
Int. Ed. 1998, 37, 1931.
(10) Whilst the catalytic asymmetric hydrogenation of â-substituted itaconate
half esters leading directly to succinic half esters such as 2 has not previously
been reported, the corresponding reduction of unsubstituted itaconate half
esters is known: Kawano, K.; Ishii, Y.; Ikariya, T.; Saburi, M.; Yoshikawa,
S.; Uchida, Y.; Kumobayashi, H. Tetrahedron Lett. 1987, 28, 1905.
(11) Jeffery, T. Tetrahedron Lett. 1991, 32, 2121.
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
363

Scheme 3. Process chemistry route to UK-370,106 (1)a
of (12), under standard hydrogenation conditions. Both [(S,S)-
Et-DUPHOS)Rh(COD)]BF412 and [(S,S)-(Fc-4-Et)Rh(COD)]-
BF413 proved efficacious for the asymmetric reduction of the
free carboxylic acid (12), giving the desired 2-alkyl succinate
(2) in >98% conversion and 96% enantiomeric excess (100:1
substrate:catalyst ratio, 60 psi H2, methanol, ambient tem-
perature). Pleasingly, for the case of the [(S,S)-(Fc-4-Et)Rh-
(COD)]BF4 catalyst, the reaction proceeds in good conversion
at a substrate:catalyst ratio of 1000:1, with an enantiomeric
excess of 94%. When the cyclohexylamine salt (13) was
utilized as substrate, both [(S)-BINAP-Ru-(p-cymene)Cl]Cl14
and [(S)-Cl-OMe-BIPHEP-Ru(C6H6)Cl]Cl15 proved effective,
giving the desired succinate in 86% and 92% enantiomeric
excess, respectively (100:1 substrate:catalyst ratio, 60 psi H2,
methanol, 60 °C). Similar enantioselectivities were observed
for [(S)-BINAP-Ru-(p-cymene)Cl]Cl-catalyzed hydrogena-
tions of inorganic salts (e.g., sodium) or other organic salts
(e.g., 1-adamantanammonium) of (12), under identical condi-
tions. Conversely, salts of (12) proved to be poor substrates
for catalytic rhodium complexes, whilst the free acid (12)
proved to be a poor substrate for cationic ruthenium
complexes. Such observations are consistent with recently
published mechanistic insights into ruthenium- and rhodium-
catalyzed asymmetric hydrogenations.16 Methanol was the
solvent of choice for all catalysts described, since other
solvents resulted either in poor enantioselectivity or poor
conversion to the desired product. In general, increasing the
temperature or pressure, or both, of the reactions led to a
decrease in enantioselectivity, whilst a decrease in temper-
ature or pressure led to extended reaction times and
ultimately poor conversion. Significant quantities of the
desired 2-alkyl succinate (2) have been prepared from the
cyclohexylammonium itaconate (13) utilizing the readily
available [(S)-BINAP-Ru-(p-cymene)Cl]Cl catalyst. The
hydrogenation proceeds in good conversion and in 88%
enantiomeric excess, giving a 65% yield of the cyclohexyl-
amine salt (15) in >98% enantiomeric excess, after a single
crystallization from ethyl acetate/methyl ethyl ketone.
With an efficient and practical synthesis of the 2-alkyl
succinate (2) in hand, significant quantities of the active
pharmaceutical (1) were prepared by utilizing a modified
medicinal chemistry protocol. Thus, the cyclohexylamine salt
(13) was broken to the free acid, which was coupled with
the dipeptide (3) by the action of 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride, in the presence
of 1-hydroxybenzotriazole and Hunig’s base. The amide
product (9) is an oil and was therefore deprotected directly
by the action of TFA in dichloromethane, giving 75% yield
a Conditions: (i) tBuOK, THF, tert-butyl bromoacetate, rt; KOH, H2O, THF,
-10 °C, 60%; (ii) allyl alcohol, Pd(OAc)2, P(o-tolyl)3, Bu4NCl, NaHCO3, MeCN,
reflux; Na2S2O5, MeOH, H2O, 64%; (iii) tBuOK, (10), THF, tBuOH, 0 °C; EtOAc,
C6H11NH2, 61%; or K3PO4, H2O, PhCH3, rt; tBuONa, (10), PhCH3, 0 °C;
adamantanamine, PhCH3, rt, 67% (iv) [(S)-BINAP-Ru-(p-cymene)Cl]Cl, MeOH,
H2O, H2 (60 psi), 60 °C, 65%; (v) 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide‚HCl, (3), HOBT, iPr2NEt, CH2Cl2, rt, quantitative; (vi) TFA,
CH2Cl2, rt; crystallized from EtOAc, 75%.
of potassium tert-butoxide, led smoothly and selectively to
the trans-â-substituted itaconate (12), in around 61% yield
following crystallization as the cyclohexylamine salt (13).
The cis isomer was not observed by NMR spectroscopy.
With quantities of the desired â-substituted itaconate (12)
in hand, we were able to screen a range of catalytic
asymmetric hydrogenation conditions for the preparation of
the enantiomerically enriched target 2-alkyl succinate (2).
This work was done both in-house and in collaboration with
Chirotech Technology Limited. A range of chiral phosphine-
modified rhodium and ruthenium complexes were screened,
for the reduction of both the free acid and a number of salts
(12) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518.
(13) Berens, U.; Burk, M. J.; Gerlach, A.; Hems, W. Angew. Chem., Int. Ed.
2000, 39, 1981.
(14) Hidemasa, T. Eur. Pat. Appl. 0673911A1, 1995.
(15) Neugebauer, T. Chim. Oggi 2002, 20, 2.
(16) (a) Gridnev, I. D.; Higashi, N.; Asakura, K.; Imamoto, T. J. Am. Chem.
Soc. 2000, 122, 7183. (b) Ohta, T.; Takaya, H. Noyori, R. Tetrahedron
Lett. 1990, 31, 7189. (c) Chan, A. S. C.; Chen, C. C.; Yang, T. K.; Huang,
J. H.; Lin, Y. C. Inorg. Chim. Acta 1995, 234, 95. (d) Holz, J.; Kadyrov,
R.; Borns, S.; Heller, D.; Borner, A. J. Organomet. Chem. 2000, 603, 61.
(e) RajanBabu, T. V.; Radetich, B.; You, K. K.; Ayers, T. A.; Casalnuovo,
A. L.; Calabrese, J. C. J. Org. Chem. 1999, 64, 3429. (f) Pavlov, V. A.
Russ. Chem. ReV. 2002, 71, 33.
364
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development

Figure 1. X-ray crystal structure of the cyclohexane in situ solvate of UK-370,106 (1), illustrating the planar framework and large
hydrophobic pores running through the structure.
of the desired material (1), over two steps, following
crystallization from ethyl acetate. The material was isolated
as a single diastereoisomer, in good purity, and with no
entrainment of heavy metals derived from the asymmetric
hydrogenation.
compound exhibits several polymorphic forms, which are
similar in lattice energy, with a characteristic melting point
of 188-191 °C. Crystallization of (1) from ethyl acetate was
shown to lead to a drug substance of inconsistent form. An
X-ray structure of (1) was elucidated from a single crystal
grown from acetone/cyclohexane (Figure 1). The data
indicate that the compound crystallizes in planar sheets, based
on a backbone of hydrogen bonding amide and acid
functionalities, with large hydrophobic pockets formed by
the biarylpropyl groups. Within the hydrophobic space, large
pores exist as channels down the crystal framework. In the
case of the single crystal grown from acetone/cyclohexane,
cyclohexane molecules occupy (or are entrained within) this
space. This has been observed for a number of solvents,
which can be easily driven from the pores by gentle heating.
We have therefore termed such composites “in situ solvates”.
The several polymorphic forms of (1), which can be
generated by crystallization from different solvents, can
putatively all be characterized by the same planar structure,
but differ in the distance between planes and therefore the
size of the hydrophobic pores. Some level of control may
be gained from the initial in situ solvate generated in solution,
which determines the size of the hydrophobic cavity prior
to a de-solvation process upon isolation and drying of the
compound. In support of this theory, we have observed that
recrystallization from ethyl acetate/methanol mixtures leads
consistently to a single form, with a characteristic powder
X-ray diffraction (PXRD) pattern. Conversely, recrystalli-
zation from ethyl acetate/tetrahydrofuran mixtures leads
consistently to a different form, again with a characteristic
PXRD pattern. In this manner, the final polymorphic form
Subsequent modifications and process improvements are
ongoing in readiness for further scale-up. First, the olefination
reaction is heterogeneous in nature, leading to concerns of
scale-up effects in the future. In a revised process, the hy-
droxy sulfonate (11) was broken to the corresponding free
aldehyde by the action of aqueous potassium phosphate in
toluene. The free aldehyde was then reacted with the phos-
phonosuccinate (10) to provide the trans-â-substituted itacon-
ate (12) in a homogeneous reaction promoted by sodium tert-
butoxide. The itaconate product was isolated as the 1-ada-
mantanamine salt (14) in an improved 67% yield. Preliminary
studies suggest that asymmetric hydrogenation of the 1-ada-
mantanamine salt (14) proceeds smoothly to yield the desired
2-alkyl succinate (2), in good conversion and high enantio-
meric excess. This reduction will be further developed to
identify optimal conditions for a commercial process. In ad-
dition, the coupling and deprotection protocols for the prepar-
ation of (1) will be changed to a more economic process.
1,1′-Carbonyl diimidazole has shown some promise as a
reliable and cost-effective reagent for the coupling of the
2-alkyl succinate (2) and the dipeptide (3), whilst an aqueous
hydrochloric acid deprotection of the amide (9) is likely to
be preferable to the current trifluoroacetic acid conditions.
In addition to the synthetic challenges encountered within
the UK-370,106 (1) program, we also modified the final
crystallization process to gain control of solid form. The
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
365

of (1) can be controlled in the final crystallization process.
A further insight into the behavior of UK-370,106 (1) solid
forms can be gleaned from the X-ray crystal structure (Figure
1). The crystal planes are aligned such that a “greasy”
hydrophobic plane, with very little noncovalent bonding (no
hydrogen bonds), can allow the planes to slip, leading to a
degree of plasticity. This has been observed empirically by
compaction simulation and nanoindentation studies, which
illustrate very low hardness and a low yield stress.
In summary, an efficient and practical asymmetric syn-
thesis of UK-370,106 (1) has been demonstrated, expedited
by an olefination/hydrogenation strategy used to access
quantities of the enantiomerically enriched 2-alkyl succinate
(2). Whilst the revised process is of similar overall yield to
that of the original Medicinal Chemistry synthesis, the route
benefits from several crystalline intermediates, allowing
control of process impurities, and can be operated safely
within parameters readily achievable on scale. This has
facilitated the preparation of bulk quantities of (1) for use
in toxicology and clinical trials, with complete control over
solid form.
min to a solution of tert-butyl bromoacetate (11.5 kg, 59.0
mol) in THF (28 L), between 0 and 5 °C, under nitrogen.
The mixture was stirred at 0-5 °C for 1 h, and then
demineralised water (6.1 L) and ethanol (30 L) were added.
A solution of potassium hydroxide (4.2 kg, 75.0 mol) in
demineralised water (84 L) was added over 2 h, between
-5 and 0 °C, and the mixture was stirred at -10 °C for 16
h. A solution of citric acid (16.5 kg, 85.8 mol) in deminera-
lised water (32 L) was added, and the mixture was
concentrated in vacuo to a volume of 180 L. Ethyl acetate
(90 L) was added, the organic phase was separated, and the
aqueous phase was re-extracted with ethyl acetate (30 L).
The combined organic phases were washed with water (30
L) and then stripped and replaced with cyclohexane by
distillation at atmospheric pressure, at a constant volume of
72 L. tert-Butyl methyl ether (18 L) was added, and the
mixture was stirred at ambient temperature for 12 h and then
filtered. The residue was washed with a mixture of cyclo-
hexane (16 L) and tert-butyl methyl ether (3.6 L), and then
dried in vacuo for 16 h to give the phosphonoacetate as a
1
colorless solid (10.0 kg, 60%); mp 120-122 °C. H NMR
(300 MHz, CDCl3) δ ) 4.20-4.10 (4H, m), 3.49-3.36 (1H,
m), 3.00-2.85 (1H, m), 2.72-2.60 (1H, m), 1.20 (9H, s),
1.37-1.27 (6H, m). 13C NMR (100 MHz, CDCl3) δ )
170.78, 170.06, 81.83, 63.90, 41.66 (d), 32.88, 28.37, 16.68
ppm. FTIR νmax 2990, 1726, 1147, 1019, 756 cm-1.
Experimental Section
(2S)-Amino-3,3-dimethyl-N-[(1S)-2-methoxy-1-phenyl-
ethyl]butanamide Hydrochloride (3). 1-[3-(Dimethylami-
no)propyl]-3-ethylcarbodiimide hydrochloride (25.4 g, 0.13
mol) was added in one portion to a stirred mixture of
1-hydroxy-1,2,3-benzotriazole (20.2 g, 0.13 mol), N-meth-
ylmorpholine (14.4 mL, 0.13 mol), (S)-(2-methoxy-1-phen-
yl)ethylamine (19.1 g, 0.13 mol), and BOC-(S)-tert-leucine
(27.8 g, 0.12 mol) in dichloromethane (600 mL), at 4 °C,
under nitrogen. The mixture was allowed to warm to room
temperature, where it was stirred for 3 h. The mixture was
washed with 5% aqueous citric acid (2 × 500 mL) and
saturated aqueous sodium bicarbonate (2 × 500 mL) and
then concentrated to a volume of 250 mL. Dioxane (250 mL)
was added, and the mixture was cooled to 0 °C. Hydrogen
chloride gas was bubbled through for 1 h, until the solution
was saturated. The mixture was allowed to warm to room
temperature where it was stirred for 1 h. The mixture was
concentrated in vacuo, and the residue was re-stripped from
diethyl ether (3 × 200 mL) to give the dipeptide (36.3 g,
4-Bromo-2-methyl-1,1′-biphenyl (4).5 A stirred solution
of 5-bromo-2-iodotoluene (668 g, 2.25 mol), phenylboronic
acid (302 g, 2.47 mol), palladium (II) acetate (25 g, 0.11
mol), and triphenylphosphine (59 g, 0.22 mol) in acetone (8
L) and aqueous sodium carbonate (2 M, 3.3 L) was heated
to reflux for 12 h, under nitrogen. The mixture was allowed
to cool to room temperature, and then toluene (7 L) and
deionised water (7 L) were added; the mixture was stirred
at room temperature for 12 h. Further toluene (2 L) was
added, and the organic layer was separated. The aqueous
fraction was re-extracted with toluene (2 × 1 L). To the
combined organic phases were added deionised water (4 L)
and concentrated hydrochloric acid, with stirring, until the
solution reached pH 1. The organic layer was separated,
washed with water (4 L), and then concentrated in vacuo to
leave a brown oil. Hexane (10 mL/g) was added to give a
brown slurry, and the mixture was stirred at room temper-
ature for 20 min and then filtered. The filtrate was concen-
trated in vacuo to leave a brown oil. Purification by
distillation gave the title compound (446 g, 80%) as a
colorless oil; bp 120-127 °C/1 mmHg. 1H NMR (400 MHz,
CDCl3) δ) 7.42-7.26 (7H, m), 7.09 (1H, d, J ) 8 Hz),
2.25 (1H, s) ppm. 13C NMR (100 MHz, CDCl3) δ ) 141.06,
140,97, 137.82, 133.20, 131.49, 129.22, 129.01, 128.42,
127.33, 121.31, 20.79 ppm. Anal. Calcd for C13H11Br: C,
63.18; H, 4.49. Found: C, 63.36; H, 4.50. FTIR νmax 1472,
1008, 763, 670 cm-1.
1
79%) as a colorless solid; mp 197-199 °C. H NMR (300
MHz, d6-DMSO) δ ) 8.87 (1H, br d, J ) 9 Hz), 8.06 (3H,
br s), 7.41 (2H, d, J ) 7 Hz), 7.33 (2H, t, J ) 7 Hz), 7.28
(1H, d, J ) 7 Hz), 5.12 (1H, m), 3.61 (1H, d, J ) 9 Hz),
3.52 (2H, m), 3.24 (3H, s), 1.03 (9H, s) ppm. 13C NMR (100
MHz, d6-DMSO) δ ) 163.38, 136.16, 124.78, 123.94,
123.79, 71.57, 57.08, 54.80, 49.09, 29.81, 23.36 ppm. Anal.
Calcd for C15H25N2O2Cl: C, 59.89; H, 8.38; N, 9.31.
Found: C, 59.84; H, 8.34; N, 9.29. MS (thermospray) m/z
) 265.1907 (MH+). FTIR νmax 1682, 1559, 1507, 1125, 870,
705 cm-1.
3-(Diethoxyphosphoryl)succinic Acid 1-tert-Butyl Ester
(10). Triethyl phosphonoacetate (12.0 kg, 53.5 mol) was
added over 30 min to a stirred solution of potassium tert-
butoxide (7.20 kg, 64.2 mol) in THF (118 L), between 0
and 5 °C, under nitrogen. The mixture was warmed to 25-
30 °C where it was stirred for 1 h and then added over 45
Sodium 1-Hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-
propanesulfonate (11). A stirred solution of (4) (20 g, 81
mmol), allyl alcohol (14 mL, 0.20 mol), tetrabutylammonium
chloride (22 g, 81 mmol), sodium bicarbonate (17 g, 0.20
mol), palladium acetate (0.91 g, 4.0 mmol), and tri-o-
366
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development

tolylphosphine (2.5 g, 8.1 mmol) in acetonitrile (200 mL)
was heated to reflux for 1 h, under nitrogen, and then cooled.
Ethyl acetate (200 mL) was added, and the mixture was
washed with water (2 × 200 mL), aqueous citric acid solution
(10%, 100 mL), and brine (100 mL). Magnesium sulfate (20
g) and charcoal (2 g) were added, and the mixture was
filtered and concentrated to low volume. Methanol (100 mL)
was added, and a solution of sodium metabisulfite (11.2 g)
in water (20 mL) was added dropwise, over 10 min, at room
temperature. The resulting mixture was stirred at room
temperature for 16 h and then filtered. The residue was
washed with ethyl acetate (3 × 20 mL) and dried in vacuo
to leave the hydroxy sulfonate as a colorless solid (15.9 g,
125.83, 80.20, 50.46, 35.34, 34.98, 31.73, 31.46, 28.58,
25.47, 25.12, 20.90 ppm. Anal. Calcd for C30H41NO4: C,
75.12; H, 8.62; N, 2.92. Found: C, 75.02; H, 8.59; N, 2.91.
FTIR νmax 2980, 1721, 1695, 1160, 702 cm-1.
(E)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-bi-
phenyl-4-yl)-2-pentenoic Acid Adamantanamine Salt (14).
A solution of potassium phosphate (32.0 g, 0.152 mol) in
water (100 mL) was added dropwise over 20 min to a
suspension of (11) (25.0 g, 76.1 mmol) in toluene (300 mL)
and water (200 mL) at room temperature. The mixture was
stirred at room temperature for 16 h, and the organic phase
was separated, washed with water (100 mL), and concen-
trated to a volume of approximately 50 mL. The resulting
solution was added dropwise over 30 min to a solution of
sodium tert-butoxide (22.4 g, 0.233 mol) and (10) (22.2 g,
71.5 mmol) in toluene (150 mL) between -10 and 0 °C,
under nitrogen. The mixture was stirred between -10 and 0
°C for 3 h, and then aqueous citric acid solution (10%, 150
mL) was added in one portion. The organic phase was
separated, washed with water (150 mL), and dried by
azeotropic distillation at a volume of 300 mL toluene. The
reaction was cooled to 35 to 40 °C, and a solution of
1-adamantanamine (10.6 g, 70.4 mmol) in toluene (100 mL)
was added over 5 min. The mixture was cooled to ambient
temperature where it was stirred for 18 h. The mixture was
then cooled to 5 °C where it was stirred for 1 h and then
filtered. The residue was dried in vacuo at 40-45 °C to leave
1
64%); mp 170-178 °C. H NMR (400 MHz, d6-DMSO) δ
) 7.49-7.30 (5H, m), 7.11-7.04 (3H, m), 5.26 (1H, br d),
3.84-3.78 (1H, m), 2.81-2.70 (1H, m), 2.20 (3H, s), 2.12-
1.99 (1H, m), 1.85-1.74 (1H, m) ppm. 13C NMR (100 MHz,
d6-DMSO) δ ) 141.94, 141.80, 139.28, 134.96, 131.08,
130.03, 129.61, 128.77, 127.29, 126.64, 82.71, 34.49, 31.95,
21.10 ppm. Anal. Calcd for C16H17NaO4S: C, 58.53; H, 5.22.
Found: C, 57.93; H, 5.25. Sulfate ashes 21.35% (expected
21.6%). FTIR νmax 1214, 1180, 1033, 767, 702 cm-1.
(E)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-bi-
phenyl-4-yl)-2-pentenoic Acid Cyclohexylamine Salt (13).
A solution of potassium tert-butoxide (6.6 kg, 59 mol) in
THF (22 L) was added over 1 h to a stirred solution of (11)
(4.55 kg, 13.8 mol) and (10) (4.94 kg, 15.9 mol) in THF
(5.2 L) and tert-butyl alcohol (18.3 L), between -5 and 0
°C, under nitrogen. The mixture was stirred between -5 and
0 °C for 4 h, and then a solution of citric acid (12.0 kg, 62
mol) in demineralised water (28 L) was added in one portion.
The pH was adjusted to pH 4-5 by the addition of aqueous
sodium hydroxide solution (40%), and the organic phase was
separated. The organic phase was concentrated in vacuo to
a volume of approximately 25 L and then recombined with
the aqueous phase. Ethyl acetate (28 L) was added, and the
organic phase was separated and then washed with a solution
of sodium bicarbonate (3.18 kg) in demineralised water (45
L). Demineralised water (15 L) was added, and the pH was
adjusted to pH 4-5 by the addition of a solution of citric
acid (2.27 kg) in demineralised water (23 L). The organic
phase was separated, washed with demineralised water (14
L), and then azeotropically dried by distillation at atmo-
spheric pressure at a constant volume of 56 L. The mixture
was cooled to 35 to 40 °C, and cyclohexylamine (1.10 kg,
11.1 mol) was added in one portion. The mixture was cooled
to ambient temperature where it was stirred for 18 h. The
mixture was then cooled to 0 °C where it was stirred for 2
h and then filtered. The residue was washed with ethyl acetate
(5 L) and then dried in vacuo at 40-45 °C to leave the
itaconate as a colorless solid (4.1kg, 61%); mp 133-135
1
the itaconate as a colorless solid (27.0 g, 67%). H NMR
(400 MHz, CDCl3) δ ) 7.41-7.05 (9H, m), 3.28 (2H, s),
2.80-2.76 (2H, m), 2.58-2.52 (2H, m), 2.26 (3H, s), 2.15-
2.11 (3H, m), 2.00-1.98 (6H, m), 1.70-1.66 (6H, m), 1.45
(9H, s) ppm. 13C NMR (100 MHz, CDCl3) δ ) 172.79,
170.95, 142.01, 140.81, 139.85, 135.45, 131.90, 130.46,
130.05, 129.42, 128.20, 126.81, 125.84, 125.49, 80.14, 51.29,
41.12, 36.16, 35.33, 34.95, 31.47, 29.56, 28.56, 20.89 ppm.
Anal. Calcd for C34H45NO4: C, 76.80; H, 8.53; N, 2.63.
Found: C, 76.90; H, 8.53; N, 2.51. MS (thermospray) m/z
) 532.3422 (MH+). FTIR νmax 2909, 2853, 1731, 1521,
1388, 1145, 704 cm-1.
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-bi-
phenyl-4-yl)-pentanoic Acid Cyclohexylamine Salt (15).
A stirred solution of (13) (1.1 kg, 2.3 mol) and [(S)-2,2′-
bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ru-
thenium chloride (2.2 g, 2.4 mmol) in methanol (8.2 L) and
water (2.8 L) was heated to 60 °C, under hydrogen (60 psi),
for 40 h and then allowed to cool to room temperature
(enantiomeric excess ) 88%). The mixture was concentrated
in vacuo to a volume of 3 L, and then ethyl acetate (5 L)
was added. The mixture was distilled at constant volume of
ethyl acetate until water droplets appeared in the distillate.
The mixture was then cooled to ambient temperature, and
then demineralised water (2.9 L) and citric acid (485 g, 2.5
mol) were added. The organic phase was separated and
washed with demineralised water (1.1 L) and then dried
azeotropically by distillation at a constant volume of 8.25
L. Methylethyl ketone (8.25 L) was added, and the mixture
was warmed to 40 °C. Cyclohexylamine (228 g, 2.28 mol)
was added in one portion, and the mixture was allowed to
1
°C. H NMR (400 MHz, CDCl3) δ ) 7.42-7.30 (5H, m),
7.16 (1H, d, J ) 7.6 Hz), 7.15-7.05 (2H, m), 6.83 (1H, t,
J ) 7.2 Hz), 3.29 (2H, s), 2.50-2.43 (2H, m), 2.26 3H, s),
2.03-1.98 (2H, m), 1.78-1.71 (2H, m), 1.61-1.57 (1H, m),
1.44 (9H, s), 1.30-1.10 (5H, m) ppm. 13C NMR (100 MHz,
CDCl3) δ ) 173.37, 171.14, 142.00, 140.84, 139.86, 139.17,
135.45, 132.21, 130.45, 130.06, 129.42, 128.20, 126.81,
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
367

cool to ambient temperature where it was stirred for 16 h.
The mixture was filtered, and the residue was washed with
a mixture of ethyl acetate (55 mL) and methyl ethyl ketone
(55 mL) and then dried in vacuo at 45 °C to leave the
succinate as a colorless solid (0.71 kg, 65%). 1H NMR (400
MHz, CDCl3) δ ) 7.42-7.25 (5H, m), 7.11 (1H, d, J ) 7.6
Hz), 7.08-7.00 (2H, m), 2.90-2.82 (1H, m), 2.67-2.58 (4H,
m), 2.30 (1H, br dd), 2.23 (3H, s), 2.00-1.86 (2H, m), 1.80-
1.50 (7H, m), 1.41 (9H, s), 1.38-1.09 (5H, m) ppm. 13C
NMR (100 MHz, CDCl3) δ )181.40, 172.54, 142.18, 141.59,
139.54, 135.17, 130.58, 129.93, 129.42, 128.20, 126.75,
125.98, 80.08, 50.51, 44.93, 38.99, 36.27, 32.89, 31.76,
30.06, 28.62, 25.47, 25.10, 20.92 ppm. Anal. Calcd for
C30H43NO4: C, 74.81; H, 9.00; N, 2.91. Found: C, 74.83;
H, 9.02; N, 3.01. MS (thermospray) m/z ) 482.3261 (MH+).
Enantiomeric excess, 98.4% by HPLC (Chiralpak AD 250
mm × 4.6 mm, rt, 95% hexane/5% IPA containing 0.1%
TFA, 1 mL/min, detection 220 nm). FTIR νmax 2931, 2860,
1732, 1573, 1406, 1135, 705 cm-1.
(3R)-3-{(1S)-1-[(1S)-2-Methoxy-1-phenyl-1-ethyl]car-
bamoyl-2,2-dimethyl-1-propyl}carbamoyl-6-(2-methyl-
1,1′-biphenyl-4-yl) Hexanoic Acid (1). A solution of (15)
(3.0 kg, 6.23 mol) in dichloromethane (15 L) was washed
with aqueous citric acid solution (10%, 2 × 15 L) and water
(15 L) and then dried by azeotropic distillation at constant
volume of dichloromethane. The mixture was cooled to 0-5
°C, and the dipeptide (3) (1.97 kg, 6.55 mol), 1-hydroxy-
benzatriazole hydrate (1.05 kg, 7.77 mol), and di-isopropy-
lethylamine (1.65 kg, 12.8 mol) were added. 1-[3-(Dimeth-
ylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.31 kg,
6.83 mol) was added, and the mixture was allowed to warm
to room temperature where it was stirred for 16 h. The
mixture was washed with a solution of sodium bicarbonate
(0.44 kg, 5.25 mol) in water (12.5 L), aqueous citric acid
solution (10%, 12.5 L), and demineralised water (12.5 L)
and then dried by azeotropic distillation at constant volume.
The mixture was combined with a second batch to give a
solution of (9) in dichloromethane (assumed quantitative
yield, 13.91 mol in 33.5 L). To this mixture was added
trifluoroacetic acid (8.74 L) over 15 min, at 20-25 °C, under
nitrogen. The mixture was stirred at 20-25 °C for 16 h,
and then dichloromethane (22 L), THF (10.9 L) and
demineralised water (22 L) were added. The pH was adjusted
to 2-3 by the addition of aqueous sodium hydroxide solution
(5 M, 13 L). The organic phase was separated, washed with
demineralised water (22 L), and dried by azeotropic distil-
lation at a constant volume of 32 L, replacing the solvent
with THF. The mixture was filtered to remove any specks,
and then the solvent was stripped and replaced to ethyl
acetate by distillation at atmospheric pressure, at a volume
of 55 L. The mixture was allowed to cool to ambient
temperature over 10 h, and the resulting suspension was
filtered. The precipitate was washed with ethyl acetate (5.5
L) and then dried in vacuo at 40 °C to leave the acid (1)
(6.0 kg, 75% over two steps) as a colorless crystalline solid;
1
mp 178-180 °C. H NMR (400 MHz, CDCl3) δ ) 7.39-
7.16 (13H, m), 7.09-7.04 (2H, m), 6.94 (1H, s), 5.16-5.12
(1H, m), 4.42 (1H, d, J ) 8 Hz), 3.63 (2H, d, J ) 4 Hz),
3.34 (3H, s), 2.75-2.69 (2H, m), 2.51-2.39 (3H, m), 2.19
(3H, s), 1.69-1.41 (4H, m), 1.03 (9H, s) ppm. 13C NMR
(100 MHz, CDCl3) δ ) 172.70, 171.12, 167.98, 139.16,
137.99, 136.44, 136.42, 131.71, 127.24, 126.46, 126.04,
125.24, 124.88, 124.15, 123.60, 123.45, 122.71, 72.13, 57.89,
54.93, 50.07, 39.61, 33.99, 32.36, 31.55, 29.60, 25.83, 23.33,
16.82 ppm. MS (thermospray) m/z ) 573.3323 (MH+); Anal.
Calcd for C35H44N2O5: C, 73.40; H, 7.74; N, 4.89. Found:
C, 73.42; H, 7.70; N, 4.92. FTIR νmax 3300, 2960, 2930,
1711, 1639, 1543, 700 cm-1.
Acknowledgment
We thank Terrence Silk, Yousef Hajikarimian, Ian Moses,
Dimitris Papodopoulos, Jonathan Fray, Jon Bordner, and
Alan Pettman of Pfizer Inc. and Mark J. Burk, Christopher
J. Cobley, Arne Gerlach, and Ian C. Lennon of Chirotech
Technology Ltd, Dow Chemical Company Ltd, for their
contributions.
Received for review January 2, 2003.
OP034001Y
368
•
Vol. 7, No. 3, 2003 / Organic Process Research & Development