Note: Descriptions are shown in the official language in which they were submitted.
105~6~
S P E C I F _ I C A T I Q N .: . ~
.'. :.
BACKGROUND OF TIIE: INVENTION
This invention rela~es to a novel process for pre-
paring 4-aminopyridines wherein the a~ino group in the 4-
position is present in free or substituted ~orm.
The products of this process are acylating catalysts -
and are intermediates for the production of active medicinal
agents. Typical of medicinally active agents obtained from 4-
aminopyridine are e~ters of steroidal hydroxyl groups e.
DOS 2,137,856 (German Unexamined Laid-Qpen Application). ~ -~
In selective or rapid acylation o~ amines (see, L.M. ` ;~
Litvinenko et al., Chem. Abs. 68, 6832~u (1968) and alcohols
(see, W. Steglich and G. ~loefle, "Angew. Chemie" 81, 1001 -~
:. .
(I969); Tetrahedron Letters 4727 (1970); and Synthesis, 1972,
619), customary acyla~ing catalys~s are 4 dialkylaminopyridines,
especially ~-dimethylaminopyridine as disclosed in DOS 1,958,954 ~
and DOS 2,137,856. KnQwn methods for the preparation of sub- ~ -
stituted 4-aminopyridines are unreliable. ~equired starting
2~ materials can be prepared only by several, expensive steps,
for example, amination of 4-chloropyridine with dimethylamine
at 150 C. under pressure, L. Pentimalli, Gazz~ Chim. Ital.
902 (196l~) 1 reaction of silylated 4-pyridone with amines, such- nS
pyrrolidine, u~ing acidic catalysis, ~I. Yorbrueggen, "Angew. `~
Chemiell 84, 348 (1972). or conversion of 4-pyridylphenyl ether
,
by reaction with ~
,~
.. ' , ,~ . '~ . ':
~ S4~
,
secondary amines to the corresponding 4-dialkylaminopyridines, '~
D. ~,erchel et al., "Chem. Ber." 91 1266 (1958). , ~ -
It has been found in accordance with this invention '' ,;.
that 4-aminopyridines can be prepared, i,n a technically feasible ,',~
, ,.~ . . -
method, simply and directly from readily accessible 4-pyridyl~
pyridinium chloride or a salt thereof, preferably the hydro~
chloride, by reaction with an easily obtainable acid amide. .,
SWI~IARY OF THE INVENTION
''" ~ ~ '.',, .
This invention relates to a method of preparing an .
aminopyridine o~ Formula I
Rl /R2
comprising the step of heating a mixture of 4-pyridylpyridinium '
chloride or a salt thereof, and an acid amide of Formula II
R~
N - Z II '~ : :
R2
wherein Rl and R2 each'are hydrogen or lower alkyl or, collect- "~ ?
15 ively with the nitrogen atom to whlch they'are attached, form a
~-, 6~, or 7-membered saturated ring containing O to 2 additional ~ '
hetero atoms, and wherein Z is -CO-R3 ana R3 is hydrogen, lower ~ .:
.
.. ... . , . - . , .
~S9~6~
::
/ R4 ~ ~ and R~ and R5 are hydrogen,
lower alkyl, to produce an aminopyridine of the formula ~ -
1\ / 2
~ ` . ', .
. ~ N
wherein Rl and R2 have the values given aboveprovided that,
uhen R3 is -N ~R4 or -PO (N ~ 412~ Rl and R2 are the s~me
as R4 and R5".
. , , ,
' ,.. .
. ~
DETAILED DESCRIPTION
- , ' , ~:
Y i~ R2~ R3, R4, and R5 are straight~
chain and branched, saturated hydrocarbon residues of 1-6
carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec.-butyl, pentyl, hexyl, tert.-butyl. Those
of 1-4 carbon atoms are preferred. Rl and R2, together with the ^;
nitrogen to which they are attached form a S-, 6-, or 7-membered
heterocyclic ring which can contain one or more additional hetero ~-
atoms. Preferably the ring contains one further hetero atom,
such as N, O or S. Preferably, the heterocyclic substituent is
hydrogenated, such as pyrrolidine, piperidine, N4-alkyl piper-
azine with alkyl as for Rl - R5 ,morpholine, thiomorpholine, and` ;~
azepine. Those having 5 or 6 ring members are preferred. ~-
- 3 -
~054604 ~ ~
Especially suitable as the acid amides o Formula II
are amides of medium strong and weak acids, preferably those of
formic acid, acetic acid, carbonic acid, and phosphoric acid.
Examples of suitable acid amides include, but are not
limited to dimethylformamide, dimethylacetamide, tetramethylurea, -
hexamethylphosphoric triamide, N-formylpyrrolidine, N-formyl- :
piperidine, N-formylmorpholine, N-methylformamide, N-methyl-
acetamide, formamide, urea, and acetamide. ::
- Salts of 4-pyridylpyridinium chloride which can be used
10 include salts with strong inorg~nic or organic acids, o.g. :~
preferably hydrochloric, sulfuric9phosphoric, benzene or
p-toluene sulfonic acid, methane sulfonic acid .
Also, exemplary of salts which can be used are qulfate, hydrogene
sul~ato and hydrochloride.
The hydroehloride is preferred. `
`~
The preferred processes of this invention are those
for preparing compounds of Formula I wherein~
(a) Rl and R2 eaeh are hydrogen;
(b) Rl and R2 eaeh are alkyl of 1-6 carbon atoms;
(e) Rl and~R2 together with the N to which they are
attaehed form a 5-7-membered saturated heterocyclic ring con- ~ ;
taining 0 to 2 additional hetero atoms;
:
~05~604
.
(d) Rl and R2 collectivcly are tetramethylene;
~1 and R2 collectively are pentamethylene;
(f) Rl and R2 collectively are hexamethylene;
(g) Rl and R2 collectively are -CH2CH2OCH2CH
(h) Rl and R2 collectively are -CH2CH2SCH2C~12-; : ~
(i~ Rl and R2 collectively are -C~12Cll2N-CH2CH2- and ;: ~:
R6 is hydrogen or alkyl of 1-6 carbon atoms. :
: (j) Z in Formula II is -COR3 and R3 is hydrogen or ;~
10 alkyl of 1-6 carbon atoms, including (a)- (i); ~ :
(k) Z is -COR3, R3 is -N and R~ and R5 are~
~ `
hydrogen or alkyl of 1-6 càrbon atoms, including (a) - li); and
. : (1) Z is -COR and R is ~.:
3 3 :~
I5
( ~ R~ and R~ and R5 are hydro~en or alkyl of 1-6 car-
bon Atonls~ incl~ding (a)-(i). ~ ~;
~: : : - The preparation of preferred compounds of this inven-
tion, wherein Rl and R2 collectively form a heterocyclic ring,
it will be understood that heterocyclic rings su~stituted by `
; alkyl of 1 - 6 carbon atom~, aralalkyl of up together 10 carbon
. atoms and aryl groups, e.g. phenyl, naphthyl.
~ . .
25 and e~uivalents thereof, are within the scope of the invention.
: The acid amide of Formula II used normally also serves
simultaneously as solvent for the reaction, but an inert organic ~ ~
solvent can be added to the reaction mixture as a diluent and/or ~ ;
solubili~er. If the acid amide is~present in solid form, .;
- 5 -
-,
.
~0546;0~
the reaction takes place in the melt or in the presence of an
inert organic solvent. The reactants can be used in molar ;
amGunts, but preferably the acid amide is used in excess, pre-
ferably 1-5 equivalents. The reaction takes place at an ele-
vated temperature, e.g., at the boiling temperature of the acid
amide or solvent employed, preferably at 120-220 C.
To attain optimum yields of the desired product, it is
advantageous to remove the pyridine formed during the reaction
continuously from the reaction mixture, for example, by a short
distillation column. The reaction is terminated when about ].
mole of thus-formed pyridine has been distilled off. The pro-
duct of this process is isolated in the usual way, for example,
by adding an excess of an aqueous al~cali, preferably 2-3 moles,
to the reaction mixture, and separat:ing the product by steam
distillation or exhaustive extraction, e.g., with methylene
chlaride.
;~Without further elaboration, it is believed that one ~Z
skilled in the art can, using the preceding description, utilize
the present invention to its fullest extent. The following
20~ preferred specific embodiments are, therefore, to be construed ~ ~
as merely illustrative, and not limitative of the remainder of ~ -
the disclosuro in any way whatsoever.
- 6 -
- :: ~, .: .. . .. . .
~054~6~
EXAMPLE 1
229 g. tl mole) of crude 4-pyridylpyridinium chloride
hydrochloride (Org. Synthesis Coll., V, 977) was dissolved in
146.2 g. (2 moles) of dimethylformamide at about 140-150 C.
Under agitation, the reaction mixture was heated for 2 hours at
a bath temperature of 1~0 C., thus removing by distillation
90 ml. of crude pyridine (b.p. 111-122 C.). The dark residue
was allowed to stand with 100 g. of NaOH in 1 liter of H2O,
and then the mixture was filtered off from the dark, insoluble
residue, and the residue and solution were extracted exhaustively
with methylene chloride. After drying the methylene chloride
extracts (Na2SO4) and treatment with a small amount of carbon,
68.3 g. (56%) of crude 4-dimethylaminopyridine was obtained,
melting at 112-113 C. after recrystallization from diisopropyl
ether.
EXAMPLE 2
The procedure of Example 1 was followed, except that
174 g. (2 moles) of dimethylacetamide was utilized in place of
~ 146.2 g. (2 moles) of dimethylformamide. After heating the
reaction mixture and working same up analogously, the yield
was 74.2 g. (61%) of 4-dimethylaminopyridine. ~;
EXAMPLE 3
The method of Example 1 was employed, except for
using 2-3 moles of tetramethylurea instead of the dimethyl- ~ ~
formamide. Yield: 56% of ~-dimethylaminopyridine, m.p. 112~113Cr ~ '
- 7 -
.. . ., . . . :
~5~6~4
EXAMPLE 4
229 g. (1 mole) of 4-pyridylpyridinium chloride hydro-
chloride in 179 g. (1 mole) of hexamethylphosphoric triamide
was heated under agitation for 1 hour to 220 C. while the --
pyridine is being distilled off (40 ml.). After cooling, the
residue was taken up in 500 ml. of H2O and heated for 1.5 hours
on a steam bath. The slightly acidic solution (pH about 5)
was filtered by way of a soft, folded filter, and the insoluble
brown proportion was washed twice with respectively 100 ml. of
.~ .
2N HCl. The combined filtrate was made strongly alkaline with
about 200 ml. of 40% KOH and was extracted exhaustively with
methylene chloride. After drying (Na2SO4) and evaporation,
the thus-remaining viscous oil (107.59 g.) was extracted with
~ 1.5 liter of diisopropyl ether and treated with a small amount ~
of carbon. From the filtrate there crystallized, at 4 C., ;;
65.79 g. (53.8%) of pure 4-dimethylaminopyridine,
m.p. 112-113 C.
EXAMPLE 5
Under agitation, 22.9 g. (0.1 mole) of crude 4-
pyridylpyridinium chloride hydrochloride in 30 g. (0.3 mole) of
N-formylpyrrolidine was heated for 3.5 hours to 180 C., while ~;~
pyridine was distilled off. The dark residue was allowed to
stand overnight with 250 ml. of 2N NaO~ and extracted ;~
exhaustively with methylene chloride. The extracts yielded,
after drying (Na2SO~), carbon treatment, and evaporation,
11.5 g. of a brown oil which was repeatedly extracted wlth
; ~
~54~;09!~
me-thylene chloride/hexane. The extracts were recrystallized
from hexane, thus obtaining 8.95 g. (60.5%) of 4-pyrrolidino-
pyridine, m.p. 55-57 C.
EXAMPLE 6
22.9 g. (0.1 mole~ of crude 4-pyridylpyridinium
chloride hydrochloride was heated in 33.9 g. (0.3 mole) of
N-formylpiperidine and then worked up as described in Example 3;
recrystallization from ligroin yielded 4.35 g. (58%) of
4-piperidinopyridine, m.p. 81 C.
EXAMPLE 7
With complete analogy to Examples 5 and 6, the reac- -
tion of 4-pyridylpyridinium chloride hydrochloride with N-
formylmorpholine prod~lced, in a 59~ yield, 4-morpholinopyridine,
m.p. 93-95 C. (from ligroin).
EXAMPLE 8
344 g. (1.5 moles) of crude 4-pyridylpyridinium chlor-
ide hydrochloride was heated under agitation in 241 g. (4.2 moles)
of N-methylformamide for 2.5 hours to 190 C., removing 120 ml.
.. .
of pyridine by distillation. After cooling, the black residue
was allowed to stand in 100 ml. of 3N NaOH for 16 hours and then
exhaustively extracted with methylene chloride. After drying ~ ~ -
(Na2SO4), treatment with a small amount of carbon, and evapora~
tion, the yield was 85 g. (52.5%) of crude, yellowish,crystalline
4-methylaminopyridine, melting at 121-124 C. after recrystal-
lization from toluene.
;
.~ ': .
~:
_ 9 _
~ '
iL854~;0~L
EXAMPLE 9
The procedure of Example 8 was followed, except
that N-methylacetarnide was used in place of N-methylformamide.
Yield: 53% of 4-methylaminopyridine, m.p. 121-124 C.
EXAMPLE 10 `
115 g. ~0.5 mole) of 4-pyridylpyridinium chloride
hydrochloride was heated in 100 ml. (2.5 moles) of formamide
under agitation to 150 C., resulting in a complete solution of
all compounds, and the solution washeated gently and gradually
to 180 C. (the solution is very frothy!), while pyridine was
distilled off. After one hour at 180 C., the reaction mixture
was cooled, heated for 3 hours on a steam bath with a solution
of 120 g. of NaOEI in 500 ml. of ~l2O, and filtered over glass
wool. The insoluble residue was washed with methylene chloride
and the black, alkaline filtrate was extracted
continuously with methylene chloride, yielding 24.9 g. (53~)
of 4-aminopyridine, m.p. 156-158 C.
EXAMPLE 11
This example was carried out analogously to Example lO
except that acetamide was employed instead of formamide.
.
Yield: 58% of 4-aminopyridine. ~ ;
EXAMPLE 1
The procedure was followed as described in Example 10,
reacting 4-pqridylpyridinium chloride hydrochloride with 3-5
equivalents of urea. Likewise, with vigorous foaming, 4-amino-
pyridine was obtained at 160-180 C. in a yield of 63~,
m.p. 156-158 C.
'
- 10 -
,.
~os~
The preceding examples can be repeated with similar
success by substituting the generically and specifically de~
scribed reactants and/or operating conditions of this invention
for those used in the preceding examples.
From the foregoing description, one skilled in the art
can easily ascertain the essential charac-teristics of this in-
vention, and without departing from the spirit and scope thereof, ~`
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
