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Patented Nov. 12, 1946
2,410,940 1
Max Ho?’er, Nutley, N. J ., assignor to Ho?’mann
La Roche, Inc., Nutley, N. J ., a corporation of
New Jersey
No Drawing. Original application September 2,
1941, Serial No. 409,298. Divided and this ap
plication May 11, 1945, Serial No.‘ ‘593,317. In L
Switzerland September 2, 1940
2 Claims.
' l
(Cl. 260-:297)
The present invention concerns the synthesis
year 1915, page 691; Monatshefte fur C‘hemie, vol.
36, year 1915, page 736). The desired reaction
consequently only succeeds in presence of free
of vitamin B6 (adermin) of the formula:
alkalis. Curiously enough, the hydrazine'formed
thereby. goes into the alkaline solution, from
which it can be-precipitatedby neutralization of
the alkali by means of free acids, ammonium salts
or acid salts.
I have found that the compound of 2-methyl-4
The 2-methyl-4-phenoxymethyb 5 .-cyavno,—.’6,
chloro-pyridine-3rcarboxylic acid hydraz'ide (III)
phenoxymethyl-5—cyano-6 -hydroxy - pyridine-3
carboxylic acid (I) is an advantageous starting
material for this synthesis. It is prepared by
thus obtained is converted into the azide‘, by
nitrousacid or materials developing nitrousacid
successively treating the condensation product,
during the reaction, and the azide boiled with
obtained from malonic acid dinitrile, phenoXy
alcohols either after its isolation or in the reac
acetaldehyde-hydrate and acetoacetic ester, with 15 tion- mixture to form 2-methyl-3-carbalkoxya
an acid and a reducing agent, in accordance with
mino -4-phenoxymethyl-5-cyano-6echloro ‘- pyri
Example 3 of any co-pending application S. N.
409,298, ?led September 2, 1941, entitled HEY
droxy-pyridine derivatives and process for the
manufacture of same.
By treatment with phosphorus-pentachloride
the 2-methyl- 4 -phenoxymethyl- 5-cyano-6-hy
trated by the following formulae:
v) I
(IJH2OC5H5 ‘
PO15' Nc-/,\-o0o1
l I NHzNHz
Z (‘)1
N/fcHa ,
ation of- the cyanogroup to the aminomethyl
However, the working, is therebyeffected almost
exclusively with palladium orplatinum as catalyst,
25 in acid solution.
On working in neutral solution
1 and with nickel catalysts, on the other hand, sec
ondary amines are mostly obtained (Helvetica
Chimica Acta, vol. 5, year 1922; page 937; vol. 6,
year 1923, page 880; vol. 8, year 1925, page 848).
30 Ithas now-been found that 2-methyl-3-carbal
koxyamino-4-phenoxymethy1- 5,-cyano-6-chlcro
pyridine, under suitableconditions, can also be
reduced to the corresponding primary amine with
nickel catalysts. Thereby, the chlorine atom in
35 position 6 is simultaneously replaced by hydro
gen.» This course of the reaction could not be
anticipated, for no case has become known so
far where a chlorine atom adhering to a pyridine
- (13112005115
methyl-5-arninomethyl-pyridine. Thehydrogen
group has often been-described in the literature
droxy-pyridine-3~carboxylic acid (I) is converted
chloro-pyridine-3-carboxylic acid chloride (II)
into , 2-methyl- B-oarbalkoxyamino- 4 -_phenoxy
into _ Z-methyl- 4 -phenoxymethyl - 5 - cyano - 6
and hydrazine caused to act thereon in the pres
ence of free alkalis. The reaction can be illus
This. compound can be converted inone step
radical has been replaced by hydrogen by means
40 of nickel as a catalyst.
It Was rather to be ex
' pected that chlorine would be obstructive during
the hydrogenation (Adkins Reactions of Hydro
gen With Organic Compounds over Copper-Chro
It is surprising that it is possible to introduce
miumoxide and Nickel Catalysts, Wisconsin, year
the hydrazine radical in the side-chain in posi 45 1937, page 54; Schwoegler, Journal of the Amer
tion 3 without the halogen reacting in the a-posi
ican Chemical Society, vol. 61, year 1939, page
tion, although it is known that a-halogen sub
stituted pyridine derivatives can react easily with
hydrazine (Journal of the Chemical Society of
London, vol. 103, year 1913, page 1978,; ,vol. 107,
The 2-methyl-3-carbalkoxyamino-4-phenoXy-i
methyl-5-aminomethyl-pyridine is converted into
. 4,
of caustic soda is added dropwise to the benzene
S-hydrOXymethyI-pyridine (IV), by causing to act
solution of the acid chloride while stirring,'
thereon nitrous acid or materials developing ni
whereby the temperature is suitably kept below
trous acid in presence of water.
30“ C. Finally, another 50 parts by volume of a
The following formulae illustrate the conver
10% solution of caustic soda are added and the
sion of said compound IV into a'dermin:
5 mixture allowed to stand for 15 minutes. The
brownish aqueous layer is removed from the hen
(‘31120 CtHs
zene layer and acidi?ed whereby the hydrazide
separates as 'a brownish, crystallinef precipitate.
For the purpose of puri?cation "the product can
be triturated with dilute ammonia and sucked
oil. Following this, it can be recrystallized from
ethyl-acetate-petroleum ether.
a colorless crystalline powder of melting point
114-115" C. Itis easily soluble in alcohol and
ethyl acetate, dii?cultly soluble in the cold in
6-ch1oropyridine-3-carboxylic acid hydrazide is
2 - methyl? - 4 - phenoxymethyl - 5 - cyano -
. onion .
It has been found in the 2-methyl-3-carbal
benzene and ether. It is di?icultly soluble in
water or petroleum ether. In dilute alkalis it is
easily soluble and can be reprecipitated by addi
tion of an acid, ammonium salts or acid salts.
koxy-amino-4-phenoxymethyl-5-hydroxymethyl-r ‘
10 parts by weight of 2-methyl-4-phenoxy
pyridine (IV) already at comparatively low tem
methyl - 5 - cyano - 6 - chloropyridine - 3 - car
peratures not only the phenoxy radical can be sa
boxylic acid hydrazide are dissolved in 50 parts
by volume of absolute alcohol, a few drops of al
coholic hydrochloric acid and 5 parts by weight
of amylnitrite added.
poni?ed by treatment with hydrogen bromide, but
also the urethane in one step. Thereby, Z-meth
yl-3-amino-4,5-dibromomethylg pyridine, {hydro
bromide is obtained. ‘By the action of water and
Crystalline precipitation of the azide quickly
nitrous acid or materials easily developing nitrous
acid, it can readily be converted into adermin 30 sets in, going into solution upon gentle heating
with evolution of nitrogen. When the evolution
of nitrogen has come to an end, the product is
(VI, 2-methyl-3-hydroxy-4,5-dihydroxymethyl
by heating.
~ '
concentrated whereby 2-methyl-3¢carbethoxy
I have also found that the aforementioned] 2
amino - 4 {phenoxymethyl - 5 - cyano - 6 - chlo
dine-3-carboiqrlic acid chloride (II) can be di- 3
rectly converted into the azide by treatment with
sodium azide, and that 2-methyl~>3-carbalkoxy
amino-4-phenoxymethyl-5-hydroxymethyl- pyri
dine (IV) , may be saponi?ed with diluted HCl’at
ropyridine separates on cooling in the form of
crystalline needles. For puri?cation purposes
the product is recrystallized from a little alcohol
or from benzene. The melting point is at 167° C.
12 parts by weight of Z-methyl-B-carbethdxy
elevated temperatures and then treated with 40 amino - 4 - phenoxymethyl - 5 - cyano - 6 - chlo
ropyridine are stirred‘ up with ‘120 ‘parts by
nitrous acid or materials developing nitrous acid,
weight of methanol,'1_2 parts by weight of~25%
for instance, silver nitrite.
aqueous ammonia and 1.2 parts by weight‘of a
It is to be noted that thevarious conversions
nickel-catalyst (R-aney nickel) in a hydrogena
of the di?erent groups may occur in one step, for
instance, the formation of the acid chloride in 3 5 tion-autoclave at a gauge pressure of 20 atm. and
position may be accomplished together with the
conversion of the hydroxy group'in 6 position into
halogen (chlorine) pyridine derivative. It‘ can‘
be done by acting upon the 2-methyl-4lpheno‘xy
acid with phosphorus pentachloride. >
Y 1 T ’
Furthermore, the hydrogenation of the cyano
group into the amino methyl .group‘may‘ take
place concurrently with thelsubstitution 'ofxthe
halogen by hydrogen, or the splitting. off of the
simultaneously slowly heated to' 60° C.‘ 3' mols of
hydrogen are quickly taken up whereupon the
hydrogenation is completely ?nished.‘ The prod
uct is allowed to cool, separated from the cata
I - lyst and the
entirely colorless ?ltrate dried in
to vacuo. The residue is taken up in 100 parts by
volume of water, small quantities of vundissolved
material ?ltered oil,‘ the ?ltrate rendered acid to
v ‘ Congo paper with dilute hydrochloric acid and
‘ again evaporated to dryness in vacuo.
The resi
phenoxy radical-by saponi?cation='may occur sié 55 due is recrystallized from ethanol. The result
ing di-hydrochloride of 2-methyl-3-carbethoxy
multaneouslya with the 'saponi?cation . of l'the
amino - 4 - phenoxymethyl - 5 - aminomethyl urethane into
the Example
amine. ‘‘ I ' ' >
20 parts by weight of ‘ 2-methyl-4-phenoxy
. , pyridine melts at 238° C.
60 ‘ 90% of the theoretical.
The yield amounts to
10 parts by weight of 2-methy1-3-carbethoxy
methyl - 5 - cyano -- 6 - hydroxypyridine '-_ 3 _
amino - 4 - phenoxymethyl - 5 - amino - methyl
carboxylic acid are. heated with 35 parts; by
pyridine-hydrochloride are dissolved in 100 parts
by volume of 5% hydrochloric acid, the solution
weight of phosphorus-pentachloride and 50:‘Parts
by weight of phosphorus-oxychloride or withgang
heated and a solution of 5 parts by weight of so
other indifferent gsolvent under’, reflux, untiliall 65 diumnitrite in water added dropwise at 90-95° C.
has gone into solution andthe hydrogen-chloride
After the evolution of nitrogen and oxides of ni
evolution has ceased. The solventand the'phos
trogen has ceased the product is allowed to cool
phorus-oxychloride formed are _distilled off in
and rendered alkaline with ammonia. The com
vacuo as completely as possible and the crystal- ‘ pound ?rst separates as an oil and becomes'crys
line residue, representing theacid chloride of 2-‘ 70 talline on standing.‘ It is sucked-off and recrys
methyl - 4 - phenoxymethyl - 5 - cyano ,-_,6 -'
tallized from benzene. >2-methyl-3-carbethoxy
ch1oropyridine-3-carboxylic acid,-_ taken up ‘in
amine - 4 - phenoxymethyl - 5 — hydroxymethyl
about 200 parts by volume of warm benzene. _A
pyridine forms white prismatic needles of melt-;
solution of '7 parts by'weight of hydrazine-hy
drate in 100 parts by volume of a 10% solution 75 ing point 127° C.
4 parts by weight of Z-methyI-B-carbethoxy
for one hour during which the azide gradually
precipitates. 100 parts of water are added to
assist complete precipitation and the precipitate
is suction ?ltered after some time, and is washed
with water and then with a little cold alcohol. It
is suspended in 300 parts of alcohol with stirring
and is converted into the 2-methyl-4-phenoxy
amino - 4 - phenoxymethyl - 5 - hydroxymethyl
pyridine are heated with 40 parts by volume of
hydrobromic acid (about 50%) for 10 minutes at
65-70° C. until the CO2 development is terminat
ed. The product is now evaporated in vacuo al
most to dryness, allowed to crystallize overnight
and taken up with alcohol in which the bromo
methyl~5-cyano-G-chlor-urethane and worked
compound is di?icultly soluble and is sucked off.
up into adermin, both as in Example I.
By concentration of the mother liquor further 10
Example III
quantities of the bromo-compound are obtained.
This is dissolved in 100 parts by volume of wa—
31.5 parts of 2-methyl-4-phenoxymethyl-5
ter and boiled for 20 minutes. Thereupon 10
hydroxymethyl-pyridine-3—urethane are heated
parts by volume of 3-n hydrochloric acid are
in 500 parts of 2.5% hydrochloric acid to 1'70
added and 1.5 parts by weight of freshly prepared 15 180° C-. for 5 hours. The brown solution is decol
silver nitrite quickly added while stirring at 90°
orized with animal charcoal and is stirred up
C. After the cessation of evolution of nitrogen
with 18 parts silver nitrite at ‘YO-80° C'. The sil
and oxides of nitrogen the product is ?ltered
ver chloride is ?ltered off and the solution is con
oiT from silver bromide and silver chloride and
centrated in vacuo during which time adermin
concentrated in vacuo. The residue crystallizes
crystallizes from the solution.
spontaneously, if need be upon rubbing with ace
This application is a division of my earlier ap
tone, and proves to be vitamin Bra-hydrochloride
plication Serial Number 409,298, ?led September
(adermin) of melting point 206—207° C.
2, 1941.
What I claim is:
Example [I
32 parts of the 2-methyl-4-phenoxymethyl-5
cyano - 6 - chloro - pyridine - 3 - carboxylic acid
1. The compound 2 - methyl - 3 - carbalkoxy
amino - 4 - phenoxymethyl — 5 - hydroxy - meth
chloride melting point 155-157“ which has been
2. The compound 2 - methyl - 3 - carbethoxy
prepared according to Example I are dissolved by
amino - 4 - phenoxymethyl - 5 - hydroxy - meth
200 parts by volume dioxane while stirring. The
yl-pyridine, having a melting point of about
solution is cooled to 5° C. and is dropped at that 30 127° C.
temperature into a solution of 10 parts of sodium
azide in 50 parts of water. Stirring is continued
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