Note: Descriptions are shown in the official language in which they were submitted.
13J059
Process And Tntermed~ates nor (S)-a-Pm'no-1
carboxvcvclopentaneacetic Acid
Field of the Invention
This invention relates to processes for preparing
amino acid and peptide derivatives. The amino acid
and peptide derivatives are useful intermediates in
the synthesis of herpesvirus ribonucleotide
i0 reductase inhibiting compounds.
Backaround of the Invent~~n
Herpes viruses inflict a wide range of diseases
against humans and animals. For instance, herpes
simplex viruses, types 1 and 2 (HSV-1 and HSV-2),
are responsible for cold sores and genital lesions,
respectively; varicella zoster virus (VZV) causes
chicken pox and shingles; and the Epstein-Barr
z~ virus (EBV) causes infectious mononucleosis.
Inhibitors of herpesvirus ribonucleotide reductase
have been found to exhibit antiherpes activity.
Indeed, several reports of peptide derivatives
,,5 having inhibitory activity against the herpesvirus
ribonucleotide reductase enzyme have bean reported.
For example, see the following references:
E.A. Cohen et al., US patent 4,795,740, January 3,
so 1989,
~' ~'~~~~'
R. Freidinger et al., US patent 4,814,432, March 21,
1989,
P. Gaudreau et al., J. Med. Chem. 1990, 33, 723,
J. Adams et al., European patent application
411,334, published February 6, 1991,
R.L. Tolman et al., European patent application 412,
595, published February 13, 1991,
L.L. Chang et al., Bioorg. Med. Chem. 1992, 2, 959,
P.L. Beaulieu et al., European patent application
560 267, published September 15, 1993,
N. Moss et al., J. Med.Chem. 1993, 36, 3005,
R. Deziel and N. Moss, European patent application
618 226, published October 5, 1994,
N. Moss et al., B.i.aorg. Med. Chem. 1994, 2, 959,
M. Liuzzi et al., Nature 1994, 372, 695,
N. Moss et al., J. Med. Chew. 1995, 38, 3617, and
N. Moss et al., J. Med. Chem. 1996, 39, 4173.
It has recently been demonstrated that replacement
?p of an aspartic acid residue with an (S)-oc-amino-1--
carboxycyclapentaneacetic acid residue in this type
of inhibitor improved potency 50-fold (N. Moss, et
al., Bioorg. Med. Chem. 1994, 2, 959). Apparently,
the cyclopentyl group improved inhibitor potency by
strongly favoring a specific confarmation, namely
the S configuration of the aspartic acid side
chain, that facilitated binding the enzyme. This
modification also proved vital in obtaining
inhibitors with good antiviral activity in vitro
and in viva (M. Liuzzi et al., Nature 1994, 372,
L~~r~~~ f
695; N. Moss et al., J. Med. Chem. 1995, 38, 3617).
The critical importance of the (S)-a-amino-1-
carboxycyclopentaneacetic acid moiety makes a
facile enantioselective synthesis of this amino
acid derivative highly desirable.
N. Moss et al., J. Med. Chem. 1995, 38, 3617
disclose a procedure for the synthesis of a
precursor of (S)-a-amino-1-
carboxycyclopentaneacetic acid. This derivative
could readily be incorporated into peptide and
peptidomimetic inhibitors. However the synthesis
of this precursor requires carefully controlled low
temperature conditions (-78° C) and purification by
chromatography. These requirements can be
impractical for the large scale preparation of this
compound.
To circumvent these problems, a synthesis that
would avoid low temperature reactions and difficult
purificatians is required. Therefore, efficient
and low cost methods which are amenable to scale-up
are needed for the preparation of (S)-a-amino-1-
carboxycyclopentaneacetic acid.
The process disclosed herein fulfills these needs.
The present process, and key intermediate compounds
prepared by the present process, can be
3o distinguished readily from the prior art. The
- 3 -
~ac~~~,~~
intermediate campaunds of the process. possess novel
chemical structures.
Disclosed herein is a process far preparing (S)-(x-
amino-1-carboxycyclopentaneacetic acid which
comprises the following steps:
(i) reacting methyl 1-formylcyclapentanecarboxylate
with the chiral amine auxiliary (S)-a -
methylbenzylamine to obtain the corresponding
Schiff base,
(ii) reacting the Schiff base with a cyanide source
in the presence of a Lewis acid to obtain a mixture
of the a-amino nitri.les of formulae 1 and 2
Ph"N CN Ph H
~N ~,CN
C(O)OMe 11 C(O)OMe
(1 ) (2)
zo in a R:S ratio of at least 1:15-30,
(iii) subjecting the latter mixture to selective
acid hydrolysis to obtain predaminantly the amino
amide 3
- 4 -
r
H
Ph"N ,,, C(O)NH2
(3)
C(O)OMe
(iv) subjecting the amino amide 3 to hydrogenolysis
in the presence of aqueous HC1 to obtain the
corresponding N-terminal derivative 4
HzN ,, C(O)NHz
(4)
C(O)OMe
followed by hydrolysis o~ the latter compound with
excess 6 N aqueaus HCl to obtain the hydro-chloride
1o salt of (S)-a-amino-1-carbaxycyclopentaneacetic
acid; and
(v) reacting the hydrochloride salt with a base
capable of transforming the hydrochloride salt to
(S)-a-amino-1-carboxycyclopentaneacetic acid.
In a preferred process the mixture of the a-amino
nitriles o~ formulae 1 and 2, obtained according to
step (ii), is crystalized from or triturated in
hexane to give essentially, enantiomerically pure
2o a-amino nitrite 2, which in turn is subjected
serially to steps iii, iv and v to give (S)-a-
amino-1-carboxycyclopentaneacetic acid.
Preferred cyanide sources for the preceding process
include trimethylsilyl cyanide, acetone
- 5 -
cyanohydrin, diethylaluminum cyanide and potassium
cyanide.
Preferred Lewis acids for the proceding processes
include TiCl~, SnCl4, ZnCl~, trimethylsilyl
trifluoromethanesulfonate, Me3Al, Et~AlC1 and
EtA1C12.
Detailed Description of rhP Tnvention
General
(S)-a-amino-1-carboxycuclopentaneacetic acid can be
represented by the following formula
H N
,,,wC(O)OH
(5)
C(O)OH
With reference to the instances where (R) or (S) is
used to designate the configuration of a radical,
2o the designation is done in the context of the
compound and not in the context of the radical
alone.
The term "residue" with reference to an amino acid
or amino acid derivative means a radical derived
from the corresponding a-amino acid by eliminating
the hydroxyl of the carboxy group and one hydrogen
of the a-amino group.
- 6 -
c~ ~ ~ 7 .~r ~f
Process
More explicitly, the present process involves
reacting methyl 1-formylcyclopentanecarboxylate
with (S)-a-methylbenzylamine (Aldrich Chemical
Company, Inc., Milwaukee, WI, USA) to give the
ZO corresponding Schiff base under standard
conditions. Next, the Schiff base is reacted with
a cyanide source (far example, trimethylsilyl
cyanide, acetone cyanohydrin, diethylaluminum
cyanide or KCN) in the presence of a Lewis acid
(for example, TiCl4, SnCl~, ZnCl2, trimethylsilyl
trifluoromethanesulfonate (Aldrich Chemical
Company), Me3Al, Et2AlCl, EtA1C12), in an organic
solvent (for example, tetrahydrofuran,
dichloromethane, toluene, or hexane) to give a
mixture of the corresponding a-amino nitrites 1 and
2. Under these conditions, amino nitrites 1 and 2
could be reproducibly obtained in an R:S ratio of
1:15-30 with a cambi.ned yield up to 95~k (0.4 mole
scale). This degree of diastereoselectivity is
especially noteworthy for this type of reaction.
The mixture of amino nitrites 1 and 2 can then be
transformed by the aforementioned steps iii, iv, v
to give predominantly (S)-a-amino-1-
carboxycyclopentane acetic acid. Thereafter, and
2i9~~~~
if desired, the latter compound can be reacted with
di-tert-butyl Bicarbonate to provide the
corresponding N-tart-butyloxycarbonyl (N-Boc)
derivative in sufficient purity for use in
s preparing herpesvirus ribonucleotide reductase
inhibitors according to known methods; for example,
see N. Moss et al., J. Med. Chem. 1995, 38, 3617.
The procedures described hereinbefore can be
modified when the molar amounts of the starting
materials and subsequent reactants are increased
> 5.7 mole. Under these conditians, it was found
that a-amino nitriles 1 and 2 were obtained in a
more modest 1:4.5 ratio. However, a-amino nitrile
1s a can readily be separated from the undesired
isomeric a-amino nitrile 1 by one crystallization/-
precipitatian from hexane (62~ yield of pure 2).
Moreover, the concentrated mother liquors, which
Contain a higher proportion of isomeric a-amino
nitrile 1 can be readily equilibrated to a 1:4-5
ratio mixture of the a-amino nitriles of formulae 1
and 2, by stirring the mother liquid with potassium
carbonate and methanol. Crystallization of the
equilibrated product provides an additional
quantity of pure a-amino nitrile 2, typically 5~~
of the concentrated mother liquors.
The following examples illustrate further this
invention. Temperatures are given in degrees
_ g -
2Z~~~3
Celsius. Solution percentages express a weight to
volume relationship, and solution ratios express a
volume to volume relationship, unless stated
otherwise. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker 400 MHz
spectrometer; the chemical shifts (b) are reported
in parts per million. Abbreviations used in the
specification include Boc: tert-butyl.oxycarbonyl;
DMF: dimethylforrnamide; EtOAc: ethyl acetate; Et20:
1o diethyl ether, HPLC: high performance liquid
chromatography; Me: methyl; MeOH: methanol;
Ph:phenyl; TLC: thin layer chromatography.
M~thvl 1-Cvanocyolot~enranar~arhoxylate
To a 22 L flask equipped with a mechanical stirrer,
thermometer and condenser containing a nitrogen
inlet was added dry DMF (8 L) and methyl
z0 cYanoacetate (800 g, 8.07 mol). Stirring was
started and KZC03 (2.67 kg, 19.3 mol) and then 1,4-
dibromobutane (I.74 kg, 8.07 mmol) were added. The
exothermic reaction mixture (temperature increased
to 75 °C) was stirred at room temperature for 16 h
f°llowed by heating at 60-75 °C for 3 h.
Approximately 2.5 L of solvent were removed under
reduced pressure and the residue was diluted with
water (8 L). The resultant mixture was extracted
with Et20 (2 x 2 L) and the combined organic phases
3~ were washed with 1 N aqueous HC1 and brine. Drying
(MgS04), filtering and concentrating afforded an
orange liquid. This material was distilled
(fraction boiling at 80 °C, 0.7 mm Hg collected) to
provide methyl 1-cyanocyclopentanecarbaxylate as a
clear colorless liquid (953 g, 77 ~ yield). 1H-NNIR
(400 MHz, CDC13) 8 3.80 (s, 3 H), 2.29-2.22 (m, 4
H), 1.90-1.84 (m, 4 H); 13C NMR 1100.6 MHz, CDC13) 8
169.2, 119.9, 52.6, 46.6, 36.9, 24.3; EI-MS exact
mass calcd for C8H11N02: 153.0790; found: 153.0785.
zo
Methvl 1-Formvicvc7op ntanecarboxyl~te
To a 12 L flask equipged with a mechanical stirrer,
thermometer and candenser containing a nitrogen
inlet was added Raney nickel (1 kg, 50 ~ slurry in
water, as sold by the Aldrich Chemical Co.). This
material was washed with distilled water and
decanted (3 x 0.8 L). Formic acid (88 ~, 7 L) was
2o added (stirring started) followed by a solution of
methyl 1-cyanocyclopentanecarboxylate (696 g, 4.54
mol) in formic acid (88 ~, 1 L). Gas evolved and
the exothermic mixture (temperature increased to 45
°C) was stirred at 75 °C for 5 h. After the
reaction mixture cooled to room temperature and the
catalyst settled, the majority of the solvent was
decanted off through a fiberglass filter. The
residue was mixed wit:rr water (6 L) and filtered.
The collected solid was washed with water (1 L) and
3o CHZC12 (1 L) and all the filtrates were combined.
_ 1p ...
~ 3 ~ ~'~r
The aqueous phase was separated and extracted with
CHZC12 (6 L), and the combined organic phases were
washed with saturated aqueous NaHC03 and brine.
Drying (MgS04), filtering, and concentrating
afforded material that was immediately distilled
(Vigreux column, fraction boiling at 93 °C, 16 mm
Hg collected) to provide methyl 1-
formylcyclopentanecarboxylate as a clear colorless
liquid (491 g, 69 ~s yield). 1H-NMR (400 MHz, CDC1 )
s
~,~ 8 9.65 (s, 1 H), 3.76 (s, 3 H), 2.19-2.04 (m, 4 H),
1.78-1.58 (m, 4 H); 13C NMR (100.6 MHz, CDC13) $
197.0, 172.6, 64.3, 51.9, 31.0, 25.3; EI-MS exact
mass cal_cd for: C8H1303; 157.0865; found: 157.0864.
This compound has been reported previously by C. A.
i5 Davis et al., J. Org. Chem. 1993, 58, 6843.
a-Amino nT~trT~e~ 1 and 2
zo (i.e. methyl 1-{(R)-cyano-{1(S)-(phenylethyl)amino}-
methyl}cyclopentanecarboxylate and methyl 1-
{(S)cyano-{1(S)-(phenylethyl)amino}methyl}-
cyclopentanecarboxylate, respectively)
~5 To a 3 L flask equipped with a mechanical stirrer
and a pressure equalizing funnel was added under a
nitrogen atmosphere methyl 1-formylcyclopentane-
carboxylate (59.4 g, 0.378 mol), (S)-cx-
methylbenzylamine (47.0 g, 0.388 mol), hexane (1.3
3o L)~ and 4th molecular sieves (90 g). This mixture
11 -
was stirred under nitrogen at room temperature for
19 h after which time it was cooled to -5 °C (ice-
salt bath). Et2A1C1 (24 mL, 0.19 mol) was added via
a syringe followed by trimethylsilyl cyanide (56 mL,
s 0.42 mal) dropwise over 15 min. The reaction
mixture was stirred under nitrogen at -5 to 0 °C for
3 h after which time a 1 M aqueous solution of
x2co3 (700 m.L) was slowly added. The resulting
slurry was filtered through diatomaceous earth, and
to the pad was rinsed with hexane and Et20. The
organic phase was washed with brine, dried (MgSOg),
filtered and concentrated to afford a very pale
yellow oil which eventually solidified to provide a
30:1 mixture of 2 and 1 (105 g, 96 ~) as a white
1s solid. Pure 2 was readily obtained by
crystallization from hexane: mp 70-73 °C; [oc]~ 126°
(c 1.89, MeOH); 1H-NMR (400 MHz, CDC13) 8 7.35-7.25
(m, 5 H), 4.03 (br q, J = 6.5 Hz, 1 H), 3.69 (s, 3
H), 3.32 (d, J = 12.5 Hz, or br s, 1 H), 2.32-2.24
20 (m, 1 H), 2.01 (br d, J = 12.5 Hz, 1 H), 1.97-1.92
(m, 1 H), 1.88-1.81 (m, 1 H), 1.74-1.59 (m, 4 H),
1.53-1.47 (m, 1 H), 1.36 (d, J = 6.5 Hz, 3 H); 13C
NMR (100.6 MHz, CDC13) c5 175.11, 143.08, 128.52,
127.68, 127.10, 119.12, 56.59, 56.49, 54.87, 52.24,
25 35.00, 33.08, 25.54, 25.09, 24.86; EI-MS (M--CH3)
exact mass calcd far C16H1gN202: 271.1.447; found:
271.1461; Anal. calcd for C17H22N202: C, 71.30; H,
7.74; N, 9.78. Found: C, 71.16; H, 7.76; N, 9.73.
Characteristic 1H NMR signals for amino nitrile 1:
- 12 -
~i~~~4~
(400 MHz, CDC13) 8 3.91 (d, J = 12.5 Hz, 1 H), 3.74
(s, 3 H), 1.31 (d, J = 6.5 Hz, 3 H).
s Example 4
Ecxuilibration of a-Amino Nitriles 1 and 2
To a solution of crude 1 and 2 (1.3:1, 37 g, 0.13
mol) (mixture will be of varying purity depending on
1.~ the isolated mother liquors from the previous
reaction) in MeOH (300 mL) was added K2C03 (9 g, 65
mmol). The resultant mixture was stirred at room
temperature for 5 days or until the original ratio
of 1.3:1 becomes 1:-4.5 (checked by NMR). The MeOH
1s was removed under reduced pressure and the residue
partitioned between water and CH2C12. The organic
phase was washed with water, dried (MgSO ),
4
filtered, and concentrated to provide an yellow-
orange residue. This material was filtered through
2o a pad of silica, followed by rinsing with EtOAc-
hexane (1:7). The combined filtrate and washing were
concentrated. The residue was crystallized from
hexane (--2 times the volume of residue) to provide
pure 2 (15.4 g).
Example 5
Amino Amide 3 (i.e. methyl 1-{2-Amino-2-oxo-{1(S)-
(phenylethyl)amino}methyl}cyclopentanecarboxylate
- 13 _
~ ~ ~~~ i ~
To a 12 L flask equipped with a mechanical stirrer,
thermometer, and a pressure equalizing funnel was
added CHZC12 (4 L) and amino nitrile 2 (674 g, 2.35
mol). This solution was cooled below 0 °C with an
s ice salt bath, and concentrated sulfuric acid (650
mL) was added at a rate so that the reaction
temperature remained below 10 °C. The reaction
mixture, which deposits an orange gum, was stirred
below 5 °C for 7 h. Approximately 1.5 kg of ice
1~ were added to the reaction mixture, and 10 M aqueous
NaOH (2 L or until pH reaches 12) was added at such
a rate which maintained an internal temperature of
less than 20 °C. Vigorous stirring was required to
effect efficient neutralization since three layers
15 form. The aqueous phase was extracted with CH2C12
(2 x 800 mL) and EtOAc (400 mL) and the combined
organic phases were washed with =.vater and brine.
Drying {MgSC?4), filtering, and concentrating
afforded compound 3 as a white solid (642 g, 90 ~~):
2o mp 133-134 °C; [Ct]n,36° (c 2.95, MeOH); 1H-NMR (400
MHz, CDC13) b 7.33-7.25 (m, 5 H), 6.44 (br s, 1 H),
5.62 (br s, 1 H), 3.62 (q, J = 6.5 Hz, 1 H), 3.61
(s, 3 H), 3.10 (s, 1 Fi), 2.09-2.00 (m, 3 H), 1.86-
1.83 {m, 1 H), 1.66-1.49 (m, 5 H) 1.36 (d, J = 6.5
2s Hz, 3 H); 13C NMR (100.6 MHz, CDC13) 8 176.65,
175.29, 144.52, 1?.8.38, 127,19, 126.86, 64.48,
57.18, 56.91, 51.95, 33.41, 32.20, 24.86, 24.67,
24.58; FAB-MS exact mass calcd far C17H25N203:
305.1856; found: 305.1865; Anal. calcd for
- 14 -
5
C17H24N203: C, 67.08; H, 7.95; N, 9.20. Found: C,
66.96; H, 8.02; N, 9.19.
Example 6
(S)-oc-Amina-1-carboxvcyclopentanPacPr;~~ Ar;d (HCl
salt far NMR)
To a 4 L flask equipped with inlets for hydrogen
balloons and a large magnetic stirring bar was added
amino amide 3 (641 g, 2.11 mol), MeOH (4.5 L), and 2
N aqueous HC1 (1 L). 20 '~ Pd(OH)2 on charcoal (54.7
g) was carefully added. The flask was evacuated
under aspirator pressure for 10 min, and H2 gas was
introduced. The reaction mixture was stirred at
room temperature (20-22 °C) for 17 h, filtered
through diatomaceous earth, and concentrated under
2o reduced pressure to provide a white solid (578 g).
This material was dissolved in 6 N aqueous HCl (2.6
L). The solution was heated at reflux for 21 h.
Concentration under reduced pressure provided the
hydrochloride salt of (S)-a-amino-1-
carboxycyclopentaneacetic acid as a pale yellow
solid. This material was dissolved in 600 mL of
water, filtered, and the pH was adjusted to pH 4..5
with concentrated NH40H (pH meter). The resulting
white solid was collected by filtration and dried
under reduced pressure (290 g, 73 ~ yie.ld): mp >250
- 15 -
~S'~>~~~~
°C; [a]~+30.5° (c 1.10, HOAc-H20, 1:1); 1H-NMR
(400 MHz, DMSO-D6) & 11.10-7.50 (br s, 2 H), 3.69
(s, 1 H), 2.07-2.02 (rn, 1 H), 1.94-1.89 (m, 1 H),
1.74-1.43 (m, 6 H); 13C NMR (100.6 MHz, DMSO-D6) &
176.20, 169.70, 57.36, 53.99, 33.24, 32.85. 25.03,
24.28; CI-MS exact mass calcd for C8H14N04:
188.0923; found: 188.0921; Anal. calcd for C8H13N04:
C, 51.33; H, 7.00; N, 7.48. Found: C, 51.30; H,
7.04; N, 7.62.
Example 7
N-Boc Der;Vat;CTe of (~)-a-Amino-1-
carboxvcvclooentaneacetic Acid
To a solution of NaOH (15.4 g, 0.385 mol) in water
(75 mL) was added the ta.tle compound of example 6
(28 g, 0.15 mol). Upon dissolution, tert-butanol
(75 mL) was added. The resultant solution was
cooled to 0 °C. Di-tert-butyl dicarbonate (49 g,
x.22 mol, warmed to effect melting) was added
drapwise over 20 min. The pH of the reaction
mixture was maintained around 10-11 with 5 M aqueous
NaOH, and completion of the reaction was monitored
by TLC and NMR. The mixture was diluted with water
(100 mL) and extracted with Et20 (3 x 150 mL). The
aqueous phase was cooled t:o 0 °C, acidified to pH 3
by the slow addita.on of concentrated HC1, and
extracted EtOAc (3 x 150 mL). The combined organic
extracts were washed with water and brine, dried
(MgS04). filtered and concentrated to afford the N-
Boc derivative, i.e.the title compound, as a white
solid (42 g, 96 ~ yield). This material was of
sufficient purity to be used for subsequent
reactions: mp 165-167 °C; [Gt]"-19.8° (c 0.90,
MeOH); 1H-NMR (400 MHz, DMSO-D6) s 10.78 (br s, 2
H), 6.83 (q, J = 10.1 Hz, 1 H), 4.54 (d, J = 9.9 Hz,
1 H), 2.00-1.97 (m, 1 H), 1.82-1.52 (m, 7 H), 1.40
(s, 9 H) ; 13C NMR (100.6 MHz, DMSO-D6) c~ 177.12,
172.31, 155.91, 78.34, 57.64, 55.04, 34.37, 31.14,
1Q 28.12, 25.27; FAB-MS exact mass calcd for C8H14N04:
288.1447; found: 288.1440; Anal. calcd for C8H13N04:
C, 54.35; H, 7.37; N, 4.88. Found: C, 54.44; H,
7.60; N, 4.91.
_ m
