Note: Descriptions are shown in the official language in which they were submitted.
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Process and Intermediates for Preparing Nicotinamide Derivatives
Background of the Invention
This invention relates to the process and intermediates for preparing
nicotinamide
derivatives. The nicotinamide derivatives that are prepared in accord with the
present
invention are disclosed in United States Patent No. 4,861, 891 filed August
31, 1988 entitled
"Antidepressant-N-substituted Nicotinamide Compounds" and PCT Application No.
PCT/IB9800315 filed March 10, 1998 and entitled "Nacotinamide Derivatives".
The compounds and processes of the present invention are useful in the
preparation
of N-substituted nicotinamide derivatives that are selective inhibitors of
calcium-independent
phosphodiesterase and are useful as antidepressants. Such nicotinamide
derivatives are
selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of
tumor necrosins
factor (TNF).
Summary of the Invention
The present invention relates to a process for preparing a compound of the
formula:
H_N
V
H3 CH3
which comprises reacting a compound of the formula
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H
N C/CF3
I I
O
IV
C
H3C/ I \CH3
OH
with a base in an alcoholic solvent.
In a further aspect of the present invention, the compound of Formula IV is
prepared
by reacting a compound of formula
H
/CF3
N C
I I
O III
C02R
wherein R is (C,-C6)alkyl with an alkyl Grignard reactant in an inert solvent.
In a further aspect of the present invention, the compound of Formula III is
prepared
by reacting a compound of the formula:
H2N
I I
COZR
wherein R is (C,-C6)alkyl with trifluoroacetic anhydride in the presence of an
amine
base in a chlorinated solvent.
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In a further aspect of the present invention, the compound of formula II is
prepared by
reacting a compound of the formula
H2N
I
C02H
with an alcohol in acidic media to form an ester
In the process for preparing compound I, excess Grignard reagent is preferably
used.
Examples of suitable Grignard reagents are methyl magnesium chloride, methyl
magnesium
bromide and methyl magnesium iodide. The Grignard reagent is preferably methyl
magnesium chloride. The solvent is inert under the reaction conditions and is
preferably
tetrahydrofuran. The base is a carbonate preferably potassium carbonate in a
methyl alcohol
solvent. The esterifying reagent is an acetic anhydride and an amine,
preferably
trifluoroacetic anhydride and trimethyl amine in dichloroethylene. The ester
forming group is
methyl alcohol in hydrochloric acid.
The invention also relates to a novel compound of the formula
H
N C/CF3
I I
O III
C02R
wherein R is (C,-Cs)alkyl
The invention also relates to a novel compound of the formula:
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H
CF3
N C~
I I
O
IV
C
H3C/ I \CH3
OH
These novel compound are used in the preparation of intermediates for N-
substituted
nicotinamide derivatives useful as selective inhibitors of calcium independent
phjosphodiesterase and intermediates for nicotinamide derivatives useful as
selective
inhibitors phosphodiesterase type 4 (PDE4) and the production of tumor
necrosis factor
(TNF).
Detailed Description of the Invention
The new process synthesis is shown in the Reaction Scheme 1 below
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NN H
N C/CF3
I I
O
HzN Hs s
C
H3C/ I \CH3
V OH
IV
C02H
I
H
H N N C/CF3
I I
O
\
C02CH3
C02CH3
III
Aminomethyl benzoic acid compound I is treated with an alcohol in acidic media
to
transform its acid functionality group to an ester compound II. Using
acetamide group to
protect the free amine of compound II gives the trifluoroacetamide ester
compound III.
Treating the trifluoroacetamide ester compound III with methyl Grignard in an
inert solvent
gives the desired tertiary alcohol Compound IV. Reacting the acetamide
compound IV with a
carbonate base in an alcoholic solvent deprotects the tritluoroacetamide to
give the desired
amino alcohol compound V.
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The previous synthesis of compound V relied on selective methyl Grignard
addition to
4-cyanobenzoic acid methyl ester (PCT/IB9800315). This methyl G,rignard
addition gives
complex reaction mixtures and the need for chromatographic purification. The
present
process prepares large quantities of the desired amino alcohol without the
need for tedious
purification.
Compound V can be used as an intermediate with a 2-aryloxy-nicotinic acid
compound as disclosed in United States Patent No. 4,861,891 to form
nicotinamide
derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4)
and the
production of tumor necrosis factor (TNF).
These useful inhibitors of PDE4 and TNF can be administered in a wide variety
of
dosage forms.
For administration to humans in the curative or prophylactic treatment of
inflammatory
diseases, oral dosages of a compound of formula I or a pharmaceutically
acceptable salt thereof
(the active compounds) are generally in the range of 0.1 to 1000 mg daily, in
single or divided
doses, for an average adult patient (70 kg). The active compounds can be
administered in
single or divided doses. Individual tablets or capsules should generally
contain from 0.1 to 100
mg of active compound, in a suitable pharmaceutically acceptable vehicle or
carrier. Dosages
for intravenous administration are typically within the range of 0.1 to 10 mg
per single dose as
required. For intranasal or inhaler administration, the dosage is generally
formulated as a 0.1 to
1 % (w/v) solution. In practice the physician will determine the actual dosage
which will be most
suitable for an individual patient and it will vary with the age, weight and
response of the
particular patient. The above dosages are exemplary of the average case but
there can, of
course, be individual instances where higher or lower dosage ranges are
merited, and all such
dosages are within the scope of this invention.
For human use, the active compounds of the present invention can be
administered
alone, but will generally be administered in an admixture with a
pharmaceutical diluent or carrier
selected with regard to the intended route of administration and standard
pharmaceutical
practice. For example, they may be administered orally in the form of tablets
containing such
excipients as starch or lactose, or in capsules either alone or in admixture
with excipients, or in
the form of elixirs or suspensions containing flavoring or coloring agents.
They may be injected
parenterally; for example, intravenously, intramuscularly or subcutaneously.
For parenteral
administration, they are best used in the form of a sterile aqueous solution
which may contain
other substance; for example, enough salts or glucose to make the solution
isotonic.
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Additionally, the active compounds may be administered topically when treating
inflammatory conditions of the skin and this may be done by way of creams,
jellies, gels, pastes,
and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a
human. The dosage to be administered to a mammal will depend on the animal
species and the
disease or disorder being treated. The therapeutic compounds may be
administered to animals
in the form of a capsule, bolus, tablet or liquid drench. The therapeutic
compounds may also be
administered to animals by injection or as an implant. Such formulations are
prepared in a
conventional manner in accordance with standard veterinary practice. As an
alternative the
therapeutic compounds may be administered with the animal feedstuff and for
this purpose a
concentrated feed additive or premix may be prepared for mixing with the
normal animal feed.
The present invention is illustrated by the following examples, but it is not
limited to
the details thereof.
Example I
4~(2,2,2-Trifluoro-acetylamino)-methyl]-benzoic acid methyl ester
Into a 100 mL three-necked flask equipped with a NZ inlet, mechanical stirrer,
and
addition funnel was charged 4-aminomethyl-benzoic acid methyl ester
hydrochloride( 5.00
gm, 24.8 mmoles) in 50 mL CHzCl2. Triethylamine (7.3 ml, 52.1 mmoles) was
added via
syringe, and the reaction mixture was cooled to 0°C in an acetonelice
bath. The
trifluoroacetic anhydride (3.7 mL, 26.0 mmoles) was charged to the addition
funnel and added
to the reaction dropwise over 30 minutes. An exotherm to 3.1 °C
occurred. The ice bath was
removed after the addition of the trifluoroacetic anhydride and the reaction
was complete as
indicated by HPLC (Waters Symmetry C-8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254
and 205
nm). The reaction was partitioned with 50 mL H20 and then the layers were
separated. The
aqueous layer was extracted 2x 50mL CHzCl2. The organic layers were combined,
washed 1x
100 ml brine, dried (NazS04), filtered and concentrated to afford a white
solid (5.43 gm, 84%).
1 H , NMR (CDCI3, 400 MHz) d 8.01 (2H, br d, CH), 7.28 (2H, br d,CH), 4.58
(2H, br d, CHZ),
3.90 (3H, s, CH3); 13C NMR (CDCI3, 100 MHz) d 166.5, 140.8, 130.3, 130.1,
127.7, 52.2,
43.4; IR (KBr, cm-1 ) 3290, 1723, 1702, 1559, 1438; EA Theory: C 50.58 H 3.86
N 5.36 F
21.82 Actual: m.p. 70.6 °C-74.4°C.
Example II
2,2,2-Trifluoro-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-acetam ide
Into a flame dried 200 mL three-necked flask equipped with a NZ inlet,
mechanical
stirrer, and addition funnel was charged 4-[(2,2,2-trifluoro-acetylamino)-
methyl]-benzoic acid
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methyl ester (3.37 gm, 12.9 mmoles) in 135 mL THF. This was cooled to
0°C in an
acetone/ice bath. Methyl magnesium chloride (21.5 mL of 3M sol'n in THF, 64.5
mmoles) was
charged to the addition funnel and introduced to the reaction dropwise over 15
minutes. The
reaction exothermed to 7.4°C. The reaction was allowed to warm to room
temperature after
addition of the grignard reagent. The reaction was monitored by HPLC (Waters
Symmetry C-
8, 50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm) and was complete after
3.5 hours.
The reaction was then slowly quenched with NH4CI (3.45 gm, 64.5 mmoles) in 130
mL H20.
The aqueous layer was extracted 2x 250 mL EtOAc. The combined organic layers
were
washed 1x 500 mL brine, dried (Na2S04), filtered and concentrated to a pale
oil (3.11 gm,
92.6%).1 H NMR (CDCI3, 400 MHz) b 7.50 (2H, br d, CH), 7.27 (2H, br d, CH),
4.50 (2H, br d,
CH2), 1.57 (3H, s, CH3) 13C NMR (CDCI3, 100 MHz) d 149.4, 134.1, 127.9, 125.2,
112.4,
72.4, 43.6, 31.8; IR (neat, cm-1) 3300, 3092, 2977,1707, 1558, 1218; EA
Theory: C 55.17 H
5.40 F 21.82 N 5.36
Example III
2-(4-Aminomethyl-phenyl)-propan-2-of
Into a 100 mL one neck flask equipped with stir bar was charged 2,2,2-
trifluoro-N-[4-
(1-hydroxy-1-methyl-ethyl)-benzyl]-acetamide (3.11 gm, 11.9 mmoles) in 31 mL
MeOH. To
this was added KZC03 (4.11 gm, 29.75 mmoles in 9.6 mL H20. The reaction was
allowed to
stir at room temperature. The reaction was monitored by HPLC (Waters Symmetry
C-8,
50:50 CH3CN:Buffer pH=3, 1 mUmin, 254 and 205 nm) and was complete after 24
hrs. The
reaction was worked up by adding 150 mL CHCI3 and 150 mL brine. The layers
were
separated and the aqueous layer was extracted 3x 150 mL 10% MeOH/CH2C12. The
layers
were dried (Na2S04), filtered and concentrated to afford a waxy yellow solid
(1.18 gm, 60%).
Example IV
4-(1-Hydroxy-1-methyl-ethyl)-benzyl-ammonium; benzoate
To a 25 mL round bottom flask equipped with a stir bar was charged 2-(4-
aminomethyl-phenyl)-propan-2-of (184 mg, 1,12 mmoles) in 2.7 mL isopropyl
alcohol.
Benzoic acid (136 mg, 1.12 mmoles) was added and the reaction allowed to stir
at room
temperature. Solids began to precipitate immediately. After 1 hr., the mixture
was filtered and
the solids were washed with additional isopropyll alcohol. White solids (141
mg, 44% yield)
were isolated. The filtrate was allowed to stir overnight at room temperature.
A second crop
(32 mg, 10% yield) was isolated.
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