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Патент USA US2406774

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2,406,774
Patented Sept. 3, 1946
UNITED STATES PATENT OFFICE
2,406,774
SYNTHESIS OF RIBOFLAVIN AND
INTERMEDIATES THEREFOR
' Jonas Kamlet, New York, N. Y., assignor to Miles
. Laboratories,’ Inc., Eikhart, Ind, a corpora
' tion oi’ Indiana
No Drawing. Application June 28, 1943,
'
Serial No. 492,622
13 Claims.
(Cl. 260—211)
1
2
condensed with d-ribose, reduced and then sapon
i?ed to the free amine, 3,4-dimethyl, G-amino
The present invention relates to a new‘ syn- '
thesis or riboflavin. More particularly it relates
to a new process whereby 6,7-dime'thyl-9-(d-1'
phenyl-d-ribarnine.
(d) SA-dimethylaniline is condensed with d
ribityl) isoalloxazine, which is identical with the
naturally occurring ribo?avin, or vitamin B2, may 5 ribose and the resultant riboside is catalytically
reduced to 3,4-dimethy1phenyl-d-ribamine. This
be synthesized. It has for an object to provide
compound is then coupled with an aryl diazonium
a simpli?ed procedure for the synthesis of this
salt to form the 3,4-dimethyl, ?-arylazophenyl-d
vitamin, whereby some steps in the present syn
ribamine and the latter compound is reduced to
thesis may be eliminated. It has for a further
object to provide a synthesis of ribo?avin which 10 the 3,4-dimethyl, G-aminophenyl - d - ribamine.
does not require the use of the expensive and dif
‘ (Karrer et al., Helv. chim. Acta, 18, 1435 of 1935.)
This method gives the best yields of all of those
described.
In 1933, Gyorgy, Kuhn and Wagner-Jauregg,
It will be noted that all of the methods described
isolated ribo?avin and recognized its identity with
vitamin B2 (Naturwissenschaften, 21, 560-1 of 15 for the preparation of 3,4-dimethyl, 6-amino
?cultly-obtainable pentose sugar, d-ribose.
1933). Shortly afterward, the structure of this
vitamin was established to be 6,7-dimethyl-9-(d
1'-ribityl) isoalloxazine (Compound A) :
(Compound A)
,
‘
$HZ-CHOH~CHOH.CHOE'CHZOH
phenyl-d-ribamine require the use of d-ribose, or a derivative thereof. d-Ribose may be derived
from natural sources, or prepared synthetically,
but, under any circumstances, it is very di?icult
20 and expensive'to obtain. The major cost in’ the
synthesis of ribo?avin may be attributed to the
d-ribose required. In order to avoid the use of
this expensive pentose, Weygand (Berichte, 73,
1264 of 1940) made novel use of a valuable or
ganic reaction, the Amadori rearrangement. By
this method, 3,4-dimethylaniline is condensed
with d-arabinose. The resultant d-arabinoside,
in the presence of a small amount of acid at an
and it was synthesized by Karrer (Helv. chim.
elevated temperature rearranges to form the 3,4
Acta, 18, 522-35 of 1935), and Kuhn (Berichte,
68, 1765—74 of 1935).
.30 dimethylphenyl-d - isoarabinosamine, which is
then reduced in alkaline solution to the 3,4-di
The basis of both the Kuhn and‘ the Karrer
methylphenyl-d-ribamine. This compound can
processes is the condensation of 3,4-dimethyl-6
then be coupled with a diazonium salt and re
duced, as described in paragraph (11) above. Al
amino-phenyl-d-ribamine with alloxan to yield
ribo?avin. Karrer carries this condensation out
in acid solutions (U. S. Patents 2,155,555 and
though the overall yield'of 3,4-dimethyl, ‘(i-amino
phenyl-d-ribamine is low (9-10%), the raw ma
2,237,074), whereas Kuhn materially increases
the yield of that condensation by e?ecting it in
terials required for this synthesis are inexpensive.
d-Arabinose can be prepared in good yield by
glacial acetic acid solution with‘ the use of boric
acid as a catalyst (U. S. Patent 2,238,874;
Berichte, 68, 1282 of 1935). , The 3,4-dimethyl-6
submitting the low-cost and readily availablecal
40 cium-d-gluconate to a Ru?" degradation, i. e., oxi
aminophenyl-d-ribamine required for this con
densation with alloxan may be prepared by a
number of methods as follows:
(a) 4,5-Dinitro-o-Xylene is condensed with d
ribamine and reduced catalytically in aqueous» a1 K15
coholic solution (Kuhn and Weygand, Berichte,
.
(b) 3,4-dimethyl, G-nitroaniline is condensed
with d-ribose and reduced (Kuhn et al., Berichte,
68, 1765 of 1935; 70, 773 of 1937) .
(0) 3,4 - dimethyl,
6 - carbethoxyaminoaniline
Amer. 'Chem. Soc, 56, 1632 of 1934).
t
It is an object of the present invention to
improve and simplify the procedure whereby the
Amadori rearrangement may be used for the
preparation of 3,4-dimethyl, 6-aminophenyl-d
68, 1001 of 1935). The yields by this method are
too low to be practical.
dation with hydrogen peroxide in the presence
01 ferric acetate (Hockett and Hudson, Journ.
59
ribamine, as well as to provide a novel synthesis
of ribo?avin that avoids the direct use of.3,4
dimethyl, G-aminophenyl-d-ribamine, but em
ploys rather av more easily obtained precursor
thereof,
the 3,4-dimethyl,
G-aminophenyI-d
isoarabinosarnine.
»
(Karrer et al., Helv. chim. Acta, 18, 69 of 1935; 18,
According to Kuhn and Weygand (Berichte,
426 of 1935), or 3,4-dimethyl, G-acetylaminoani
70, 769 of 1937) , the Amadoriv rearrangement in
line (Karrer et al., Berichte, 68, 216 of 1935) is 55
2,406,774
3
4
volves the conversion of arylamine-N-aldosides
ylphenyl-d-isoarabinosamine (Compound D) is
into the corresponding aryl-N-isoketosamines, in
now dissolved in a suitable organic solvent (e. g.,
the presence of a small amount of acid at elevated
95% ethanol, glacial acetic acid), treated with a
small amount of decolorized carbon and ?ltered.
(b) The solution of 3,4-dimethylphenyl-d-iso
arabinosamine (Compound D) is now coupled
with a diazotized arylamine (Compound E), of
which the aryl nucleus is eventually removed,
temperatures. Thus, when the aldose is d
arabinose, the rearrangement probably goes
through the following stages, catalyzed by the
acid present:
'
' K : while a N-atom 0f the diazo linkage is retained.
10 Although any arylamine may conveniently be
used, I prefer to use an arylamine containing a
water-solubilizing group on the ring, as in p
aminobenzoic acid, and sulfanilic acid, and many
others which are available. The rationale for
15 using an arylamine bearing a Water-solubilizing
group on the ring will become evident as this
process is elaborated.
The reaction involved in this step is the fol
lowing:
-
(Compound D)
25
The Schi?‘ base (I) ?rst formed is in equilibrium
with the furanose amino-aldoside (II). The
OH:
(Compound F)
CH3
oxygen-bridge of the latter readily breaks to form
the -ol form (III) of the isoarabinosamine,
which tautomerizes to the‘keto form (IV). When
the original amine R.NI—I2 is 3,4-dimethylaniline,
the ?nal isoketosamine is the 3,4-dimethylpheny1
d-isoarabinosamine. To eiTect this rearrange
ment, 1 mole of the aldose, 1.1 to 1.4 moles of
the aryl amine and 0.002 to 0.02 mole of acid
are heated in the presence of 2 to 4 moles of
water at 70-90” C. for a few minutes. (Wey
gand; Berichte, 73, 1259—1276 of 1940.)
The
?nal product is a mixture of the arylamino-N
alcloside and the aryl-N-isoketosamine. '
In the speci?cation and claims of this inven
—NHCH2COCHOHCHOHCH20H
The mixture of the 3,4-dimethylphenyl-d-iso
arabinosamine and the diazonium salt is agi
tated vigorously at 5~10° C. for 0.5 to 1.0 hour to
effect the condensation illustrated above. The
reaction mixture is then made alkaline and a
deep reddish-brown solution and/or vsuspension
of the 3,4-dimethyl, 6-arylazophenyl-d-isoarabi
nosamine (Compound F) is obtained.
(0) The 3,4-dimethyl, G-arylazophenyl-d-iso
arabinosamine (Compound F) is now reduced in
alkaline solution. In general, two types of reduc
tion, the term “isoaribity ” (see Compound M)
ing agents may be employed; namely:
(q. v. Weygand) refers either to the Z-keto-d
1. Reducing agents that will reduce both the
aribityl or to the Z-keto-d-ribityl group, or to 45
azo-linkage
(to the amine) and the keto group
both. The only di?erence between d-arabinose
in the isoarabinosamine side-chain forming the
and d-ribose resides in the optical con?guration
corresponding secondary alcohol (Compound H).
of the asymmetric carbon in position 2. When
These agents (Compound G) include sodium
this center of asymmetry is eliminated (e. g., by
amalgam in the presence of a stream of CO2
conversion to a keto group) both cl-arabinose and 50
(to neutralize the NaOH evolved), hydrogen in
d-ribose give the same Z-ketopentose. Thus, 2
the presence of Fancy nickel, and hydrogen in
keto-d-ribityl is the same group as Z-keto-d
the presence of a reduced platinum catalyst. As
aribityl, and is here referred to as d-isoaribityl.
Weygand has postulated, reduction of the d-iso
The present invention is based on the follow
arabinosamine side chain in alkaline solution
ing sequence of reactions:
55 leads only to the desired d-ribamin (Compound
(at) 3,4-dimethy1aniline (Compound B) and d
H) (Berichte, 73, 1262 of 1940), thus:
arabinose (Compound C) are submitted to an
Amadori rearrangement. The resultant mixture
(Compound F)
of 3.4-dimethylphenyl~d-isoarabinosamine (Com
pound D) and 3,4-dimethylaniline-d-arabinoside 60 OH3(Compound D’) is then distilled with steam.
CH3
The isoarabinosamine (Compound D) is not af
fected by this treatment, but ‘the arbinoside
(Compound D’) readily hydrolyzes to give back
the original BA-dimethylaniline and d-arabinose. 65
The BA-dimethylaniline distills over with the
steam and the major portion of the amine origi
nally started with may thus be recovered for re
use.
The residue after the steam distillation com
‘ prises an oily layer of impure 3,4-dimethylphenyl
~—NH.OHB.CO.OH0H.CHOH.CH2OH
—-N=N—R
reduction
——->
(Compound G)
(Compound H)
CH
CH3
—-NH.CH2CHOH.CHOH.CHOH.CH2OH
NHQ
+ R.NH2
d-isoarabinosamine (Compound D) and an
aqueous phase from which the major portion of
The reaction mixture, after reduction, is evap
the d-arabinose originally started With may be
orated in vacuo to dryness. The residue is dis
recovered for re-use. This impure BA-dimeth 75 solved in a minimum amount of hot absolute
72,406,774
of 6,7-dimethyl, 9-(d-1'-ribityl)
(Compound P) :1
ethanol, and ?ltered from insoluble material.
If the original amine used for obtaining the di
azotized arylamine contained a solubilizing group,
isoalloxazine
(Compound M)
0112.0 O.CHOH.CHOH.OH:OH
i. e., if it was p-aminobenzoic acid, for example,
it exists in the dried residue as the alkali-metal
l
salt which is soluble in water but insoluble in the
absolute alcohol. Thus, a convenient method is
provided for the separation of the 3,4-dimethyl,
?-aminophenyl-d-ribamine (Compound H) and
the original coupling amine that was regenerated
by the reduction.
CHz-
GE's-
I
.
N-—C
17
a
//N\00
l
.
N=\ CO/NH
~
Pt
+ 2112 —---r
catalyst
(CompoundN)
(Compound 1?)
.
CHZ-CHOH.CHOH.CHOH'GHBOH
The 3,4-dimethyl, G-aminophenyl-d-ribamine
(Compound H) thus obtained may now be con
\ )‘3
verted to ribo?avin by condensation with alloxan,
as described by Karrar and Kuhn (q. v. supra) 15
.
(Compound L).
(I10
NH
O/
2. Reducing agents (Compound J) that will
reduce only the diazo linkage. These agents in
which rapidly reverts to ribo?avin (Compound A)
clude sodium hydrosul?te (Na2SzO4) in alkaline
onshaking with air (Compound Q). The cat
solution, andlnascent hydrogen in acid solution 20 alyst is, ?ltered oif and the ribo?avin isrecov
as produced by’ zinc dust in acid solution. The
ered from the alcoholic ?ltrate by evaporating
3,4 - dimethyl,
6 .. arylazophenyl - d - isoara
'to dryness in vacuo. It is obvious, of course, that
in this condensation, the use of boric acid as a
catalyst is optional, and the use of alloxan, as
binosamine (Compound F) will thus be reduced
to a new compound, 3,4-dimethyl, G-aminophen
yl-d-isoarabinosamine. (Compound K) :
mentioned in this speci?cation and claims like
wise refers to its functional equivalents, such
as dialuric acid, isodialuric acid and alloxantine.
The following examples are’ given in order to
(Compound F)
CH
—NH.CH:CO.CHOH.CHOH.CH2OH
a
CH;
de?ne and illustrate this invention but in no
way to limit it to reagents, proportions or con
reduction
N=N—R
-_-->
(Compound
J)
, ditions described therein.
CHz-
Numerous modi?ca
tions will occur to any person skilled in the art.
(Compound K)
EXAMPLE I
—'NH.CH2.00.0HOH.CHOH-CHIOH
Step 1.-Preparati0n of 3,4-dimethyl, 6-(p-car
CHr-
. NH:
+ 3.1m,
boxyphenylaeo) '
phenyl - d - isoarabinosamine
(Compound F) and (a, species of 3,4-dimethyl, '
Where the used and regenerated amine is water
soluble,_ the new compound may likewise be sep
arated from the concomitant regenerated cou
pling‘amine by evaporating the reaction mixture
to dryness and extracting with hot absolute al
cohol.
>
6-arylaeophenyl-d-isoarabinosamine)
_ A mixture of 20.0 grams of d-arabinose, 16.0
grams of 3,4-dimethylaniline (Compound B), 1.0
gram of benzoic acid and 6.0 cc. of water is heat
ed on the boiling water bath for six minutes. A
homogeneous melt is soon obtained which is a
'
(Id) The 3,4-dimethyl, ?-aminophenyl-d-iso
mixture of, 3,4-dimethylphenyl-d-isoarabinos
arabinosamine (Compound K), obtainedas de 45 ‘amine (Compound D) and 3,4-dimethylaniline
scribed in the paragraph immediately above, is
d-arabinoside (Compound D’). 100 cc. of hot
now condensed (Compound L) in glacial acetic ’
acid with alloxan in the presence of boric acid
95% alcohol is now added, and the solution is
submitted to steam distillation until the distil
as a catalyst, to yield a new compound 6,7-di
late is substantially iree of 3,4-dimethylaniline.
methyl, 9-(d-l’-isoaribityl isoalloxazine (Com 50 The residue in. the distilling flask soon sepa
pound M) :.
‘
(CompoundK)
CH3v
NH.CH'2.CO.CHOH.CHOH.CH2OH +
CH
NH:
(Compound L)
(Compound M)
CH2.CO.CHOH.CHOH.CH2OH
--NH
00
I
00
0
CH?
/
N\ C /N\
CO
co -__'
([30 llTH
~
I
CH@—
‘
/C\ )NH
-
C., then adding dropwise with constant stirring,
‘l
/
N
so
CO
rates into two phases. The aqueous phase (con
taining the major portion of the d-arabinose
originally used) is decanted and preserved. The
dark brown oily residue is dissolved in 500 cc, of
95% ethanol, 2.0 grams of decolorizing carbon is
added, the mixture is heated on the water-bath
under re?ux for 30 minutes and then ?ltered.
Simultaneously, a diazo solution is prepared
by dissolving 2.75 grams of p-aminobenzoic acid
and 4.0 cc. of concentrated hydrochloric acid in
50 cc. of ice water, chilling the solution to 5°~l0°
14.0 cc. of 10% sodium nitrite solution.
65
The ?ltered alcoholic solution of 3,4-dimethyl
phenyl-d-isoarabinosamine (Compound D) is
cooled, with constant stirring, to 10°-15° C., and ‘
The acetic acid (Compound M) is distilled oif in
vacuo, the yellow residue of impure, 6,7-dimethy1,
9-(d-1'~iscaribityl) isoalloxazine is dissolved in
the freshly prepared diazo solution (Compound
herein designated Compound N for convenience).
The 6,7-dimethyl, 9-(d—1'-isoaribityl) isoalloxa
zine (Compound M) is reduced vto the leuco form
sodium salt of 3,4-dimethyl, G-(p-carboxyphenyl
E) 'is added slowly. Stirring is continued for
a 0.2N sodium hydroxide solution in ethanol and 70 an hour, and the solution is then made alkaline
by the cautious addition of concentrated alco
the solution is hydrogenerated in the presence of
holic NaOH solution. There is thus obtained a
a reduced platinum catalyst (the agent being
dark reddish-brown solution-suspension of the
azo) phenyl-d-isoarabinosamine (Compound F).
2,406,774
7
8
The free acid may be obtained by diluting the
alcoholic solution with three volumes of water
and acidifying with acetic acid. A gummy red
dish brown material separates out which rapidly
solution. The reaction mixture is ?ltered while
hot and the ?ltrate is evaporated to dryness in
Vacuo. The dry residue is taken up in 100 cc. of
hot absolute ethanol, ?ltered from insoluble ma
solidi?es and may be comminuted to amorphous
terial and evaporated to dryness.
brown particles, In. pt. 83°—8<l° (decomp.). For
There is thus
obtained 4.1 grams of orange-colored crystals,
3,4-dimethyl, 6-(p-carboxyphenylazo) phenyl-d
m. pt. 119°-121° C. For 3,4-dimethyl, G-amino
isoarabinosamine (Compound F): N (calcu
lated) =10.5%; N (-found)=10.7%. The yield is
N (calcul-ated)=10.4%, N (found)=10.3%.
5.1 grams.
phenyl - d - i-soarabinosamine
10
Step 2.—Pre1vamtion of 3,4-dimethyl, 6-amino
phenyZ-d-ribamine (Compound H)
(Compound
K) :
Step 3.-Preparation of ribo?avin
1.05 grams of 3,4-dimethyl, G-aminophenyl-d
isoarabinosamine (Compound K) is dissolved in
The alcoholic solution-suspensionof the sodi
60 cc. of glacial acetic acid and added to a solu
um salt of 3,4-dimethyl, 6-(p1carboxyphenylazo) 15 tion of 0.95 gram of alloxan tetrahydrate (Com
phenyl-d-isoarabinosamine (Compound F), (pre
pound L) and 1.80 grams of boric acid in 60 cc.
pared in step 1) is made 0.2N with respect to
of boiling glacial acetic acid. The mixture is
free sodium hydroxide, and a catalyst prepared
from 3.0 grams ‘of chlorplatinic acid according to
gently re?uxed in the dark for 15 minutes and
the acetic acid is then distilled ed in vacuo.
the method of Adams in J our. Amer. Chem. Soc. 20
The crude residue of GII-dimethyl, 9-(d-l’
isoaribityl) isoalloxazine (Compound M) thus ob
44, 1937 (1922); 415, 2171 (1923) suspended in
alcohol, is added. Hydrogen gas (Compound G)
tained is dissolved in 200 cc. of 0.2N NaOH in
95% ethanol and ?ltered from insoluble mate
is now passed through the vigorously agitated so
lution at 25°-80° C. until the reduction is com
rial. The Adams catalyst prepared from 1.5
grams of chlorplatinic acid, suspended in alcohol,
is added and hydrogen gas is passed through the
vigorously agitated solution at 25°—30° C. until
the reduction is complete and no more hydrogen
is absorbed. The catalyst is ?ltered o? and the
?ltrate, comprising an alcoholic solution of leuco
plete and no more hydrogen is ‘absorbed. The
catalyst, as well as other insoluble material, is
now ?ltered off and the alcoholic ?ltrate is evap
orated to dryness in vacuo. The dry residue is
taken up in 100 cc. of hot absolute ethanol, ?l
tered from insoluble material and evaporated to
dryness. There are thus obtained 4.0 grams of
light orange colored crystals, in. pt. 123°—124° C.
6,7-dimethyl-9-(d-1’—ribityl) isoalloxazine (Com
pound P) is neutralized with acetic acid. It is
then aerated for an hour to oxidize the leuco base
For 3,4-dimethyl, S-aminophenyl-d-ribamine
(Compound H): N (calculated)=l0.4%; N
(Compound P) by the oxygen (Compound Q) of
(found) =10.4%.
35 the air and evaporated to dryness in vacuo. From
This 3,4-dimethyl, G-aminophenyl-d-ribamine
the crude residue, riboflavin (Compound A) may
(Compound I-l) may noW be converted to ribo
?avin by the methods of Karrer or Kuhn.
be recovered on crystallization.
It is to be observed that in Example 2 the re
EXAMPLE II
ducing agent (Compound J) is employed which
reduces only the —N=N-- group but not the
—-CO-- group of Compound F, thus producing
Compound K, which couples with the alloxan or
equivalent Compound L to form Compound M;
Step 1.——Preparation of 3,4-dz‘methyl, d-(p-c'ar
bomyphenylazo) :0henyZ-d-isoambmosamine
This step is eifected as described in Example I.
While in Example 1, a reducing agent (Compound
By acidifying the steam-distillate with hydro
chloric acid and distilling on" the solvent, 10 45 G) is used which reduces both of said groups
—-N=N— and —CO— forming Compound H,
grams of 3,4-dimethylaniline (Compound B) may
which then coupled with a Compound L provides
be recovered (as the hydrochloride), and re
Compound M’ which is similar to Compound M in
turned to the process. Similarly, from the aque_
all respects except that the -CO-- group of Com
ous phase of the distillation residue 12 grams of
d-arabinose (Compound C) may be precipitated 50 pound M is a —CHOH—- group in Compound M’.
The reducing agent Compound N reacts with
as the 2,4-dinitrophenylhydrazone. By adding
either Compound M or Compound M’ to give the
this aqueous phase to the crude solution of d
leuco product (Compound P), which is oxidizable
arabinose obtained by following the procedure of
Hockett and Hudson, immediately prior to the
' ?rst decolorization with carbon
by air to ribo?avin (Compound 1A) .
Having described my invention, what I claim
and desire to protect by Letters Patent is:
1. In the process of making ribo?avin the steps
(Jour. Amer.
Chem. Soc. 56, pg. 1633, column 1, line '7, of July,
1934), there may be recovered 10 grams of d
arabinose in addition .to the normal yield of 55
to 65 grams. Thus, the ?nal yield of 5.1 grams
of 3,4-dimethyl, 6-(carboxyphenylazo) phenyl
of reacting d-arabinose with 3,4-dimethylaniline
and thereby forming the compound 3,4-dimethyl
60 phenyl-d-isoarabinosamine, reacting the latter
d-isoarabinosamine (Compound F) is obtained
compound with a salt of a diazotized arylamine
from an overall consumption of 6.0 grams of 3,4
dimethylaniline and 10.0 grams of d-arabinose.
and thereby forming the compound 3,4-climethyl,
6-arylazophenyl-d-isoarabinosamine, and reduc
Step 2.--Preparation of 3,4-dz‘methyl, z’i-amz'no
phenyl-d-isoarabinosamine (Compound K)
ing the latter compound by the action of a re»
65 ducing agent selected from the group consisting
The alcoholic solution-suspension of the so
dium salt of 3,4-dimethyl, G-(carboxyphenylazo)
phenyl-d-isoarabinosamine (Compound F) (pre
pared in step 1) is heated under re?ux on the 70
boiling water-bath and a saturated aqueous solu
tion of sodium hydrosul?te (Compound J) is
added slowly until the dark reddish-brown solu
tion has been discharged to a dark orange color,
and there is an excess of free reducing agent in 75
of alkali metal hydrosul?tes in neutral solution
and in alkaline solution and nascent hydrogen
in acid solution thereby forming 3,4-dimethyl, 6~
aminophenyl-d-isoarabinosamine of the formula:
CH3—
—-NH.CH2.CO.CHOH.CHOH.CH:OH
2. In the process of making riboflavin the steps
2,406,774 -~
.
10$
>
of reacting, d-ar'abinose‘with ‘3,4-dimethylaniline i
6-aminophenyl-d-isoarabinosamine with alloxan
and thereby forming the compound 3,4-dimethyl
phenyl-d-isoarabinosamine, reacting the latter
in acid solution. l
‘
v
,
.,9.‘;In .a process "for the synthesis of ribo?avin,
compound with a salt of a diazotized arylamine
the; step which‘ comprises condensing 3,4-dimeth
and thereby forming the compound 3,4-dimethyl,
jyl, 6_eaminophenyl-d-isoarabinosamine‘ with al- -
6 - arylazophenyl - d - isoarabinosamine, reducing
loxanjin acetic acid solution.
the latter compound by the action of a reducing
agent selectedfrom the group consisting of alkali
metal hydrosul?tes in‘ neutral solution and in _,
alkaline solution and nascent hydrogen in acid
the step which comprises reducing 6,7-dimethyl
9-(d¢1"-is0aribityl) isoalloxazine by the action of
1,0; lira, process for the synthesis of. ribo?avin,
hydrogen acting in the presence of a hydrogena- ,
tion catalyst, anddehydrogenating the resulting
leuco-BJTV-dimethyl, 9-(d—1’-,ribityl) 'isoalloxazine
thereby forming ribo?avin.
solution thereby forming the compound ISA-‘die
methyl,‘ 6-aminophenyl-d-isoarabinosamine, and
condensing the latter compound with alloxan
11. The process of producing ribo?avin which
thereby forming 6,7-dimethyl, 9- (d-l’-isoaribityl)
comprises reacting 3,4-dimethylaniline and d
isoalloxazine of the formula:
arabinose by an Amadori rearrangement while
forming thereby 3,4-dimethyl-phenyl-d—isoara=
N
binosamine, coupling the latter with a diazonium
salt of a diazotized aromatic amine thereby form
N
\O// \('30
CH
CH:
onlooononononomon
20
ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos
amine, reducing the latter by the action of a re
\N¢ \ 00/NH
ducing agent selected from the group consisting
of (1) sodium amalgam, and (2) hydrogen acting
3. A process for the synthesis of ribo?avin
which comprises submitting 3,4-dimethy1aniline
and d-arabinose to an Amadori rearrangement,
in the presence of a hydrogenation catalyst
thereby forming 3,4-dimethyl, 6-aminopheny1
25
d-ribamine, and condensing the latter with an
coupling the resultant 3A-dimethylphenyl-d
agent selected from the'group consisting of a1
loxan, dialuric acid, isodia'luric acid and alloxan
isoarabinosamine with a diazonium salt of a, di
azotized aromatic amine to form the correspond
tine.
ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos
.
12. The process of producing ribo?avin which
comprises reacting 3,4-dimethylaniline and d
arabinose by an Amadori rearrangement while
amine, reducing the latter by the action of a re
ducing agent selected from the group consisting
of alkali metal hydrosullites in neutral solution
forming thereby 3,4-dimethylphenyl-d-isoara
and an alkaline solution and nascent hydrogen in
binosamine, coupling the latter With a diazonium
Y salt of a diazotized aromatic amine thereby form
acid solution to form 3,4-dimethyl, 6-amino
phenyl-d-isoarabinosamine, condensing the latter
with, alloxan in acid solution to form 6,7-di
ing 3,4-dimethyl, ,6-arylazophenyl-d-isoarabi
nosamine, the latter containing a benzene nu
methyl, 9-(d-1’-isoaribityl) isoalloxavzine, reduc
cleus having attached thereto the linkage
—N=N—-, reducing the —N=N— group by the
ing the latter in alkaline solution to theleuco
form of ribo?avin by the action of hydrogen act
ing in the presence of ahydrogenation catalyst,
and oxidizing said leuco form to ribo?avin.
4. In a process for the synthesis of ribo?avin,
the step which comprises reducing 3,4-dimethyl,
action of a reducing agent selected from the
group consisting of (1) sodium amalgam, (2) hy
drogen in the presence of a hydrogenation cata
lyst, (3) alkali metal hydrosuliites in neutral solu
tion and in alkaline solution, and (4) nascent
hydrogen in acid solution, thereby forming a
compound having the resulting group
6-arylazophenyl-d-isoarablnosamine to 3,4-di
methyl, U-aminopnenyl-ci-rioamine by the action
of a reducing agentselected from the group con
sisting or (1) 500111111 amalgam, and (2) hydrogen
acting in the presence of a hydrogenation catalyst.
5. In a process for the synthesis of ribo?avin,
on
the step which comprises reducing 3,4-dlmethyl, 50
CH:-
N:
—NH2
?-ip-carboxyphenylazo) phenyl-cl-isoarabinos2i
(2) hydrogen acting in the presence of a hydrog
condensing the said resulting compound with a
compound selected from the group consisting of
alloxan, dialuric acid, isodialuric acid and allox
antine, While thereby forming the essential group
enation catalyst.
ing
mine to 3,4-almethyl, 6-aminophenyl-d—ribamine
by the action of a reducing agent selected from
the group consisting of (1) sodium amalgam, and k
-
p
6. In a process for the synthesis of ribo?avin,
the step which comprises reducing 3,4-dimethyl,
?-arylazophenyl-d-isoarabinosamine to 3,4-di
methyl, '6-aminophenyl-d-isoarabinosamine by
the action of a reducing agent selected from the
group consisting of alkali metal hydrosul?tes in
neutral solution and in alkaline solution and
nescent hydrogen in acid solution.
'7. In a process for the synthesis of ribo?avin,
the step which comprises reducing 3,4-dimethyl,
6-(p-carboxyphenylazo) phenyl-d-isoarabinosa
60
CH3
I
and reducing the resulting compound by the ac
tion of hydrogen and a hydrogenation catalyst
- thereby forming the leuco base of ribo?avin from
which ribo?avin is obtained by oxidation.
13. .The process of producing ribo?avin which
comprises reacting 3,4-dimethylaniline and d
arabinose by an Amadori rearrangement while
binosamine by the action of a reducing agent se 70 forming thereby 3,4-dimethylphenyl-d-isoara
binosamine, coupling the latter with a diazonium
lected from the group consisting of alkali metal
salt of a diazotized aromatic amine thereby form
hydrosul?tes in neutral solution and'in alkaline
mine to 3,4-dimethyl, G-aminophenyl-d-isoara-g
solution and nascent hydrogen inacid solution.
8. In a process for the synthesis of ribo?avin,
ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos
amine, the latter containing a benzene nucleus
the step which comprises condensing 3A-dimethy1, 15 having attached thereto the linkage —-N=N-,
Q,406,774 '
11
‘
subjecting the resulting 3,4-dimethyl, 6-arylazo
loxan, dialuric acid, isodialuric acid and alloxan
phenyl-d-isoarabinosamine to reduction by the
tine thereby forming the essential grouping
action of a reducing agent selected from the
group consisting of (1) sodium amalgam, (2) hy
drogen in the presence of a hydrogenation cata
lyst, (3) alkali metal hydrosul?tes in neutral
solution and in alkaline solution, and (4) nascent
hydrogen in acid solution thereby at least reduc
ing the —N=N—- group to one —-NH2 group in an
aryl amino compound, subjecting the said aryl
amino compound to condensation with a com
pound selected from the group consisting of al
reducing the said essential grouping by vthe ac
tion of hydrogen in the presence of a hydrogena
10 tion catalyst to the leuco base of ribo?avin from
which ribo?avin is obtained by oxidation. 7
JONAS KAMLET.
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