close

Вход

Забыли?

вход по аккаунту

?

Патент USA US2411611

код для вставки
Patented Nov. 26, 1946
I 2,411,611
UNITED;- STATES PATENT OFFICE’
I
,
2.411.611
MANUFACTURE or N-(POLYHYDROXY
ALKYL ) -ARYLAMINES
Franz Bergel, Aaron Cohen, and John Wynne
Haworth, Welwyn Garden City, England, as
signors, by mesne assignments, to Hoffmann
La Roche Inc., Nutley, N. J ., a. corporation of
New Jersey
No Drawing. Application March 4, 1942, Serial
No. 433,341. In Great Britain May 20, 1941
5 Claims. (Cl. 260-211)
2
1
The
synthesis
of
N-(polyhydroxyalkyl)~
The N - (polyhydroxyalkyl) - arylamines are
used as intermediates in the preparation of val
arylamines, such as arabityl or ribityl xylidines,
is described in the literature (of. R. Kuhn,
uable pharmaceutical substances.
The following examples in which the parts are
Berichte der deutschen chemischen Gesellschaft,
1935, 68, 1282 and‘1'765; P. Karrer, Helvetica
Chimlca Acta, 1935, 18, 522 and 1130; 1936, 19,
by weight illustrate how the process of the in
vention may be carried into e?ect:-
264). Its main feature is the formation of a con
>
1. Preparation of N-(d-arabityl) -aniline
densation product between a sugar and the
arylamine and the subsequent or concurrent
(a) d-Arabonic acid anilide is prepared in any
10 convenient manner, for example by heating d
arabonic acid lactone with aniline, as described
The present invention provides a process which
by Th. W. J. van Marle (Rec. trav. chim. Pays
avoids the use of the sometimes di?lcultly acces
hydrogenation to the saturated compound.
Bas, 1920, 39, 549-72), for the corresponding 1
sible sugars but employs the arylamides of the
compound, or by heating the lactone with aniline
more readily available sugar acids of the general
formula I, in which the substituents R and R’ 15 in the presence of dilute acetic acid.
Alternatively the d-arabonic acid anilide may
are hydrogen or identical or different alkyl
be prepared from methvl d-arabonate: A mixture
groups and in which a: is 3 or 4. Such arylamides
of_28.5 parts of methyl d-arabonate and 15 parts
may be obtained in known manner by the inter
of aniline are heated on the waterbath. The
action-of the corresponding arylamine with an
ester or lactone or with the acids themselves 20 warm liquid mixture solidi?es after 45 minutes,
when 20 parts of methanol are added and the
which readily form the lactones.‘ According to
heating continued for another 2 hours, while the
the invention the amide is treated with an acylat
methanol evaporates. The solid mass is trit
ing agent to form the corresponding acyl com
urated with 50 parts of absolute alcohol and well
pound (II), the acyl compound is treated with
pressed on a ?lter. The crude anilide is recrys
a halogenating agent to‘ form the corresponding
tallised from 75% alcohol and has a melting
chloroimine (III) and the latter is reduced with
point of 198° C. In order to increase the yield,
hydrogen in the presence of a hydrogenation
the mother liquors are concentrated and another
catalyst to form the corresponding N-(poly
5 parts of aniline added. The heating is con
acyloxyalkyD-arylamine (IV) which ?nally is
hydrolysed to form the N-(polyhydroxyalkyD 30 tinued for several hours and the product
arylamine (V).
_
isolated in the same way as above.
~
(b) 7.5 parts of the above d-arabonic acid
‘anilide are acetylated by adding the same to a
I
R,
6.
II
R!
C3
40
~
(0) A suspension of 4.09 parts of ?nely pow
=17 (CHOAc) ,CHaOAc
III
NHCH?CHOAchCHzOA.
IV
R!
NHCH1(CHOH),CH,OH
3!
w
acetyl-d-arabonic acid_anilide, which crystallises
from alcohol in colourless needles, melting point
161° C.
Cl
R!
R
solution of 3 parts of zinc chloride in 50 parts of
After
being kept at 0° C. for 1 hour, the mixture is al
lowed to stand at room temperature for 24 hours
and poured into water, precipitating tetra
35 acetic anhydride, which is cooled in ice.
V
_ dered tetra-acetyl-d-arabonicacid
anilide
and
2.08 parts of powdered phosphorus pentachloride
45 in 50 parts of dry toluene is heated on the water
bath for 1 hour. Hydrogen chloride is evolved.
The toluene and phosphorus oxychloride are re
moved under reduced pressure. The residual oil
is dissolved in ether, ?ltered clear, concentrated,
50 and light petroleum (boiling point 40-60" C.) is
addedto the concentrate. On cooling, the cor
responding chloroimine (III, where R=R'=H)
separates in colourless needles of melting point
102° C.
((1) Catalytic hydrogenation of. the above
55
2,411,611
-
4
3
R'=CI-l’s). It separates in colourless needles,
melting point 72° C.
ohloroimine-is carried out by shaking a solution
of 1.5 parts of the ohloroimine in 40 parts of dry
ethyl acetate with hydrogen in the presence of
0.2 part of 25% palladised charcoal and 0.2 part
(e) 2.5 parts of the last mentioned tetra-acetyl
compound are mixed with a solution or 7 parts
of crystalline barium hydroxide in 150 parts of
of platinum oxide and 0.3 part of anhydrous so
dium acetate. When the hydrogen uptake is com
water and re?uxed for three-quarters of an hour.
The excess of barium hydroxide is precipitated
plete, the solution is ?ltered, evaporated to dry
ness, and the residual basic material crystallised
as carbonate from the resulting solution by the
from aqueous methyl alcohol, from which
passage of carbon dioxide. After ?ltering, the
10 clear solution is evaporated to dryness under re
N-(tetra-acetyl-d-arabityl) -aniline
duced pressure. The product is extracted from
the residue by boiling alcohol, which is then ?l
tered hot. On cooling the alcoholic extracts,
75-'l6° C.
N-(d-arabityl)-p-toluidine separates in colour
(e) 1.7 parts of the last mentioned tetra 15 less needles, melting point 179° C.
separates in colourless plates, melting point
acetyl compound are mixed with a solution of 6
3. Preparation of N-(d-ribityl)~b-toluidine
parts of crystalline barium hydroxide in 100 parts
(a) d-Ribonic acid-p-toluidide is prepared in
of water and re?uxed for three-quarters of an
hour. The excess of barium hydroxide is precip
any convenient manner. For example, a mix
itated as carbonate from the resulting solution 20 ture of 10 parts of d-ribonic acid lactone and 12
parts of p-toluidine, 100 parts of water, and 10
by the passage of carbon dioxide. After ?lter
ing, the clear solution is evaporated to dryness
under reduced pressure.
parts of glacial acetic acid is heated on the water
bath overnight in an open vessel. A solid mass
The product is ex
is formed, which is recrystallised from butyl al
tracted from the residue by boiling alcohol, which
is then ?ltered hot. On cooling the alcoholic ex
25
tracts, N-(d-arabityD-aniline separates in col
ourless needles, melting point 157-159” C.
2. Preparation of N-(d-arabityl) -t0luidine
(a) d-Arabonic acid-p-toluidide is prepared in 30
any convenient manner. For example, a mixture
of 8 parts of d-arabonic acid lactone, 10 parts of
p-toluidine, 80 parts of Water and 10 parts of
acetic acid is heated on the water bath for 24
cohol, yielding d-ribonic acid-p-toluidide, which
forms colourless needles, melting point 157-158°
C. In order to increase the yield, the butyl alco
hol mother liquors are evaporated to dryness and
the residue heated for a further 24 hours, and
the product isolated as above.
(b) 10 parts of the above d-ribonic acid-p
toluidide are acetylated by adding the same to a
solution of 4 parts of zinc chloride in 60 parts of
acetic acid anhydride, which is cooled in ice.
hours in an open vessel. A solid mass is formed 35 After being kept at 0° C. for an hour, the mix
which is triturated with alcohol, ?ltered and
washed with ether, yielding d-arabonic acid-p
toluidide, which crystallises from alcohol in col
ourless needles, melting point 199-200° C.
ture is allowed to stand at room temperature
overnight and poured into water, precipitating
tetra-acetyl-d-ribonic acid-p-toluidide, which
crystallises from alcohol in colourless needles,
(b) 7.3 parts of the above d-arabonic acid-p 40 melting point 120-121° C.
toluidide are acetylated by adding the same to a
(0) Suspension of 12 parts of ?nely powdered
solution of 3 parts of zinc chloride in 45 parts of
tetra-acetyl-d-ribonic acid-p-toluidide and '7
acetic anhydride, which is cooled in ice. After
parts of powdered phosphorus pentachloride in
being kept at 0° C. for 1 hour, the mixture is al
50 parts of dry toluene is heated gently on the
lowed to stand at room temperature overnight 4. water bath for 11/2 hours. The toluene and phos
and poured into water, precipitating tetra-acetyl
phorus oxychloride are removed under reduced
d-arabonic acid-p-toluidide, which crystallises
pressure, ?nally at 0.2 mm. 50 parts of toluene
from alcohol in colourless needles, melting point
are again added to the residue and the evapora
167-168” C.
tion is repeated under reduced pressure. The
(c) A suspension of 4 parts of ?nely powdered
?nal residue is dissolved in 60 parts of hot pe
tetra-acetyl-d-arabonic acid-p-toluidide and 2
parts of phosphorus pentachloride in 30 parts of
dry toluene is heated on the water bath for 1
hour. Hydrogen chloride is evolved. The toluene
troleum ether (boiling point 100-120° C.), the so
lution is ?ltered and the solvent evaporated un
der reduced pressure. A further portion of tolu
ene is added and the evaporation repeated once
and phosphorus oxychloride are removed under 55 more to remove the last traces of phosphorus
reduced pressure. The residue is extracted with
oxychloride. The desired ohloroimine is obtained,
dry ether, which leaves a small portion of un
as a pale yellow oil.
changed tetra-acetyl-d-arabonic acid-p-toluidide
(d) Catalytic hydrogenation of the above
ohloroimine is carried out by shaking 9 parts of
trated and light petroleum (boiling point 40-60° 60 the ohloroimine in 100 parts of dry ethyl acetate
C.) is added until the mixture is turbid. On cool
with hydrogen in the presence of 0.8 part of 25%
ing, the corresponding ohloroimine (III, where
palladised charcoal and 0.1 part of platinum oxide '
behind. The ?ltered ethereal solution is concen
R=H and R’=CH3) separates in colourless nee
dles, melting point 82° C.
and 5 parts of anhydrous sodium acetate. The
hydrogen uptake is sometimes slow at ?rst but
((1) Catalytic hydrogenation of the above 65 can be speeded up by addition of a few drops 01’
ohloroimine is carried out by shaking a solution
palladous chloride solution. When the hydrogen
of 1.6 parts of the ohloroimine in 30 parts of ethyl
uptake is complete, the ethyl acetate solution is
acetate with hydrogen in the presence of 0.05
?ltered and extracted several times with dilute
part of 25% palladised charcoal and 0.1 part of
hydrochloric acid. The acid layer is made alka
platinum oxide and 0.3 part of anhydrous sodium 70 line with sodium carbonate solution, and the basic
acetate. When the hydrogen uptake is complete,
material extracted with ether. The ether is dried
the solution is ?ltered, evaporated to dryness and
over sodium sulphate and evaporated, leaving
the residual basic material crystallised from a
N-(tetra-acetyl-d-ribityl)-p-tolu.idine as a, yel
small amount of methanol, yielding N-(tetra
low oil.
acetyl - d - arabityl) - p - toluidine
(IV,
R=H,
(e) 1 part of the last mentioned tetra-acetyl
2,411,011
5
(e) 4.5 parts of the above mentioned tetra-'
compound is mixed with a solution of 3 parts
of crystalline barium hydroxide in 50 parts of
acetyl compound are hydrolysed by mixing with
a solution of 12 parts of crystalline barium hy
water and boiled under re?ux for half an hour.
droxide in 200 parts of water and re?uxing for
The excess of barium hydroxide is precipitated
three-quarters of an hour or by dissolving in 9
as carbonate from the resulting solution by the
parts of methanol, adding 1.8 parts‘ of sodium
passage of carbon dioxide. After ?ltering, the
hydroxide in 22.5 parts of water and heating the
clear solution is evaporated to dryness under re
mixture on the water bath for half an hour,
duced pressure. The product is extracted from
during which time some of the methanol distils
the residue by boiling alcohol, which is then
?ltered hot. On cooling the alcoholic extracts, l0 ‘off. In the ?rst case, the excess of barium hy
droxide is precipitated from the resulting solu
N-(d-ribityD-p-toluidine separates in colourless
needles, which, after recrystallisation from alco
hol. has a melting point 140-141” C.
3:4-dimethyl-ani1ine separates
4. Preparation of N-(d-ribityl)-3:4
in
colourless ,
15 plates, melting point 141-143’ C., which is identi
dimethylaniline
(a) d-Ribonic
_ tion by the passage of carbon dioxide and ?ltered
hot. In both cases, on cooling, the N-(d-ribityl) -
cal in every respect with the same compound
acid-3:4-dimethylganilide
prepared in any convenient manner.
synthesised by P. Karrer (Helvetica Chimica
is
For ex
Acta, 1935, 18, 1130).
»
ample, a mixture of 5 parts of d-ribonic acid
We claim:
lactone and 5 parts of 3:4-dimethylaniline is 20
1. A process for the manufacture of N-(poly
hydroxyalkyl) arylamines, which comprises
heated on the water bath overnight. A solid is
acetylating an anilide of a sugar acid of the gen
formed, which is triturated with hot butyl alco
hol. After cooling, the product which is d-ribonic’
eral formula
‘
'
acid-3:4-dimethylanilide is ?ltered off. It crys
tallises from butyl alcohol in colourless needles,
melting point 162-163° C.
I
,
RI
(b) 10 parts of the above d-ribonic acid-3:4
dimethylanilide are acetylated by adding the
wherein a: is selected from the integers 3 and 4
same to 4 parts of zinc chloride in 65 parts of
and R and R,’ each represent a radical selected
acetic anhydride, which is cooled in ice. After so from
the group consisting of hydrogen. and a
being kept at 0° C. for 1 hour, the mixture is
lower alkyl radical, to form the corresponding
allowed to stand at room temperature for 24
acetate, chlorinating the acetate with phos
hours and poured into water, precipitating tetra
phorous pentachloride to form the correspond
acetyl-d-rioonic acid-3:4-himethylanilide, which
ing N-(polyacyloxyalkyl)-arylamine, and hy
crystallises Irom alcohol in colourless needles,w as drolyzing this compound with a non-oxidizing
melting point 114—115“ C.
hydrolyzing agent to form the N-(polyhydroxy
(c) A suspension of 10 parts of ?nely pow
alkyl) -arylamine.
dered tetra-acetyled-ribonic acid-3:4-dimethyl
2. A process for the manufacture of NF-(d
aniiide and 5.5 parts of powdered phosphorus
ribityl) -p-toluidine which comprises acetylating
pentachloride in 50 parts of dry toluene is heated 40 d-ribonic acid-p~toluidide with acetic anhydride
on the water bath at about 50° C. for 1 hour.
in the presence of zinc chloride to form the cor
The toluene and phosphorus oxychloride are re
responding acetate, chlorinating the acetate
moved under reduced pressure, a i'urtner 50 parts
with phosphorous pentachloride to form the
of toluene added and the evaporation repeated.
The residue is taken up in 50 parts of hot pe
troleum ether (boning point IOU-120° 0.), the
solution is ?ltered, and the orgamc solvent re
moved under reduced pressure. The chloro
imine remains as an oil winch solidi?es on cooling
and may be crystallised irom a mixture or‘ ether
and petroleum ether, from which it separates in
colourless needles, melting point 62“ C.
(a) Catalytic hydrogenation of the above
corresponding chloroimine, hydrogenating the
45 chloroimine with hydrogen in the presence of
palladized charcoal and platinum oxide as cat
alysts, and hydrolyzing the resulting compound
in an aqueous solution of barium hydroxide to
form the N-(d-ribityl) -p-toluidine.
to acetylating d-ribonic acid-3:4-dimethyl-anillne
3. A process for the manufacture of N-(d
ribityl) -3 : 4 - dimethylaniline which comprises
with acetic anhydride in the presence of zinc
crude chloroimine is carried out by shaking a
chloride to form the corresponding acetate, chlo
solution or 9.3 parts 01' the chloroimine in 150
rinating the acetate with phosphorous penta
parts of dry ethyl acetate with hydrogen in the as
_
chloride to form the corresponding chloroimine,
presence 01' 0.8 part 01 25% paiiadised charcoal
hydrogenating the chloroimine with hydrogen in
or 1.5 parts 01 10% paliadised charcoal and 5
the presence of palladized charcoal as catalyst
parts or anhydrous sodium acetate. The hy
and hydrolyzing the resulting compound with
arogenation can be accelerated if desired by the,
so aqueous solution of barium hydroxide to form
addition or more my ethyl acetate.
when the
the corresponding N-(d-ribityl)-3:4-dimethyl
hydrogen uptake is complete, the solution is hl
aniline.
tered, evaporated to dryness, the residue taken
,
4. A process which comprises acetylating d
up in dilute hydrochloric acid and non-basic ma
ribonic acid~3:4-dimethylaniline with acetic an
terial removed by extraction with ether. The cs hydride to form the corresponding acetate, chlo
aqueous solution is made aikaline with sodium(
carbonate solution, when the N-ltetra-acetyl-d
ribityl) -3:4-aiinetnyl-aniiine separates as an oil,
rinating the acetate with phosphorous penta
chloride to form the corresponding chloroimine
and hydrogenating the chloroimine with hydro
which quickly soiidi?es. This is extracted with
gen in the presence of a noble metal hydrogena
ether the extract washed with water, and dried. 70 tion catalyst, to form the corresponding N
The solvent is removed and the residue on cool
(tetra-acetyl-d-ribityl) -3 : 4-dimethylaniline.
ing lorms a solid crystalline mass, which after
recrystallisation irom methyl alcohol has a melt
ing point 98-99‘ C. This product is N-(tetra
acetyl-d-ribityl) - 3 :4-dimethylanilide.
5. 3.4-dimethyl-N-tetraacylribonyl~aniline.
FRANZ BERGEL.
AARON COHEN.
76
JOHN WYNNE HAWORTH.
Документ
Категория
Без категории
Просмотров
0
Размер файла
458 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа