Thrombin Inhibitors with Aminopyridyl at P1
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3733
(5), 43 mg (0.28 mmol) of HOBT, and 54 mg (0.28 mmol) of
EDC in 1.7 mL of anhydrous NMP was treated with DIEA to
pH 8.5, and the resulting solution was stirred at room
temperature in a N2 atmosphere for 8 h. The reaction mixture
was diluted with 3× its volume of water, and the suspension
stirred vigorously at room temperature for 15 min. The
suspension was filtered, and the residue was purified by
preparative HPLC using a trifluoroacetic acid (0.1%)-CH3CN
gradient. Lyophilization of pure fractions gave 135 mg (93%)
of product 14b as a trifluoroacetic acid hydrate salt.
6-Am in o-2,4-d im eth yl-3-p yr id in ylm eth yl D-3,3-Dicyclo-
h exyla la n yl-L-p r olin a m id e (14c). A solution of 128 mg
(0.22 mmol) of 6-amino-2,4-dimethyl-3-pyridinylmethyl N-Boc-
D-3,3-dicyclohexylalanyl-L-prolinamide (14b) in 10 mL of 50%
TFA/CH2Cl2 was stirred for 20 min, and the TFA was removed
under reduced pressure. The product was purified by pre-
parative HPLC using a TFA (0.1%)-CH3CN gradient. Lyo-
philization of pure fractions gave 102 mg (96%) of the title
compound 14c as a trifluoroacetic acid hydrate salt.
6-Am in o-2,4-d im eth yl-3-p yr id in ylm eth yl N-Boc-D-3,3-
d ip h en yla la n yl-L-p r olin a m id e (14d ). An amount of 108 mg
(0.25 mmol) of Boc-D-3,3-(Ph)2-Ala-Pro-OH (3b) and 75.5 mg
(0.50 mmol) of 6-amino-2,4-dimethyl-3-pyridinemethylamine
(5) were coupled with hydroxybenzotriazole hydrate (43 mg,
0.28 mmol) and EDC (54 mg, 0.28 mmol) in 1.5 mL of DMF at
pH 8.5 with DIEA. The mixture was stirred under N2 at room
temperature overnight, then diluted with 10 mL of 10%
aqueous citric acid, and extracted with CH2Cl2. The CH2Cl2
extracts were washed with aqueous Na2CO3, dried (Na2SO4),
filtered, and concentrated in vacuo to give the crude Boc
derivative of the title compound. The product was purified
by preparative HPLC using a TFA (0.1%)-CH3CN gradient.
Lyophilization of pure fractions gave 128 mg (90%) of the white
powder 14d as a trifluoroacetic acid hydrate salt.
6-Am in o-2,4-d im eth yl-3-p yr id in ylm eth yl D-3,3-Dip h en -
yla la n yl-L-p r olin a m id e (14e). A solution of 114 mg (0.20
mmol) of 6-amino-2,4-dimethyl-3-pyridinylmethyl N-Boc-D-3,3-
diphenylalanyl-L-prolinamide (14d ) in 10 mL of 50% TFA/CH2-
Cl2 was stirred for 20 min, the TFA was removed under
reduced pressure, and the product was purified by preparative
HPLC using a TFA (0.1%)-CH3CN gradient. Lyophilization
of pure fractions gave 92 mg (98%) of the title compound 14e
as a trifluoroacetic acid hydrate salt.
Ack n ow led gm en t. The authors wish to thank Dr.
A. Coddington for the fast atom bombardment mass
spectroscopy and Dr. G. M. Smith, M. Zrada, and K.
Anderson for chemical characterization. We also thank
Dr. J oel R. Huff for his support and encouragement.
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for 48 h, and evaporated to dryness under reduced pressure.
The residue was hydrolyzed with 6 N HCl at 100 °C for 4 h
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6 as a HCl salt.
2-Am in oth iop h en e-4-m eth yla m in e (7). A 300-mL flask
was dried in an oven and cooled in a dry nitrogen atmosphere.
The flask was equipped with a rubber syringe cap and a
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in THF was introduced. Then 5-nitrothiophene-2-carbonitrile
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resulting mixture was allowed to stir for 4 h at room temper-
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mixture was stirred continually overnight, filtered, and evapo-
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(FABMS: 159). A solution of 435 mg of 5-nitrothiophene-2-
methylamine in 35 mL of EtOH/4.0 mL of acetic acid/8.0 mL
of H2O was hydrogenated at 60 psi on a Parr apparatus over
500 mg of 10% palladium hydroxide on carbon as catalyst.
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pad, the residue was washed with ethanol, MeOH, and H2O,
and the combined filtrates were concentrated to provide 370
mg (94%) of amine intermediate 7 (FABMS+: 129).
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In a similar manner as 13a -e were prepared the following
compounds: 9-12, 15a -e, and 16a ,b.
J M970493R