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Патент USA US2133969

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Patented 0st. 25,1‘93e
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Edwin‘L'Buchmani'New
Research Corporation, ‘New
fork,York,v
N. NET-ya cor
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vlNn-ation ofNewYork=~~°~w
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NoDrawing. Application Mar-ch18; ‘1935, we I ;' ,-,
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7 Claims.
Serial No.
(crate-13oz)
‘ I I a ‘_
1;,
__
> This invention'relates to thiazole compounds, "*is’aisuchasbromine, chlorine or iodine,~j -
and methods of making them,- and more partlcu- ‘and R} has the same meaning as above,‘ with‘ a
larly to thiazole compounds suitableioruse in ,thiojamide compound or the typeZCSNHa,;.in._
the synthesis of the antineuritic. vitamin-and“ which Z1188 the Same sim?cance'asi?bove- The
5 methods of making’ suchcompounds.
'
, reacti?n'whlch
nlacejis bellevedtto be I'elJI'e- xii‘; ’
byInR._R.
an article
Williams,
entitled
which
“Structure
was published
of,_ vitamin
in the
B" ~ "sented by theiollowing
j _
equation:
\ ;
Cm- n‘; - g
i
Journal'ot the Americanchemical'Society,~vol.
,1
svypage 229‘ (1935);, the probable structural
1-.::>
"
.
? ’°F"?99Hx¥\+Z9sNH?->B 2y..,.=-°=—.B+H:°~ "j
10 formulae! theantineuritic vitamin, also known
its vitamin B and vitamin B1, is'disclosed.
t
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.t
t
. -
~
This
.';
1'
-\ - -
-' vitamin ‘is useful ‘,as a therapeutic agent in the
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treatment of certain__,disea'ses," among which is
1;
a t
I
‘
It is alsovuseful
as a supplement
to cer15‘ beriberi.
t'ain foodstuffs
for the promotion
of growth.
and compounds “the second t;‘ypél-tivlmghv are kndwn I I
asw-thiazolezderivatives,
may'be 3mg
readily
Prepared 15‘
well being of animals including man.- It has been by
removinggthe acids gramme
oftheserde
I 20 "
round that this vitamin is a chemical compound
which comprises‘ a > thiazole ‘derivative and _;a
mama. I
- 1g is ‘to be ‘?nder'swodtthafithe tel-in etmble ‘
pyrimidine derivative in chemical‘. combination;
object of the inv?mtmn is 150 pmvide thi?mle
compounds" as used herein ‘and in the annexed '
claims, is intended to. include both the above de- 20 '
compounds. and particularly thosevwhich are use-
scribed salts of thiazol'e‘ derivatives and the thia
‘1111 in th§synthesis °f ‘the an?neuritis vitamin 01'
zole ‘derivatives themselves‘. Also the term “thla- _
similar c("upwind-‘i-v
.
.
' a
~
-:
'
,
zolesalts” means the salts of the thiazole deriva
A further object of the invention is tov provide
?ves mentioned above_
25 ‘useful and effective methods of producingthiazole
'
communds 91' the types described
- i
'
A speci?c example; which will illustrate to per- 25 ‘
. ‘
> ‘The present invention relates to the synthesis
sons skilled in the-‘art howlthe‘ invention may
be,
practiced, is the-condensation: bftmo' form?‘
of thiazole derivatives orztheirvsalts which" re-
amlderncsmfwlthlthe' b'ro?acego propyl 8L
semble or comprise the thiazole} portion of ‘the
cohol m'vmg the formula‘,
30 vitamin B1 and which may be intermediates suit- ' ,~ , I
able for combining with pyrimidine groups or
groups capable of being converted into pyrimidine
I
'1
~
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j/
>_¢
is
. _ - _
-_
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is usually made by introducing
gigging)
d20.1fm the antineuritic vitamin or related 'I'hio
forumi'ormamide
m1d6,’ HCONHZ,
and? phosphorous pent”
' 35 -' Thiazole compounds, embodyingthe invention ’ sulphide’ P355, 111w dry-etherrshakmg 01'. “110m
have the gem?“ formulae:
'
.- _
t
t,
i4° -»
'
H"
' -
'-
> ~
CH;
_
(l;_-_C__R“
\
/
_
'. l
x:/N\
\c—
’
t
1 _ ‘ ‘
on, '
which may also bedesignated 3 brom 3 aceto '
C: __R
=
’
"and
N
\
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' V'c
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propan 101, may be prepared in accordance with
my processdescribed in the copending applica
tion,SerialN_o. 11,683,1iled March 18,1935.
i
"
the
mixture tofstandand-r‘emoving' the ether by g5 4
distillation. The" brom ~itceto'npropyl ialcohol,‘
"7
j
49
‘In, the process coveredjby- this copending ap
plication, bromine is added to a water ‘solution of vi
aceto 3-aceto
propan propan
1 01 and
the ensuing reaction
7
45 in which X represents an ionic halogen or an acid, 33 vbrom
1'; olinisprpduced.
‘ V
v 45
radical, Z'is hydrogen; an amino group, a sulfInf‘ this process the requisite‘ weights oi‘thio t.
hydryl group or other group capable ‘of-being
formamide ‘and the labovedescribed brom aceto
easily converted into‘ or“ replaced by _.,hydrogen‘," propyl alcohol are'idissolvedfinyalcohol and thef
5
and R is the group CHzCI-hOH or ancth'er'sroun; solution'ailowed to stand, after which the product -
'such as CHzCOOH, CHzCHO, QHzCQOCzHs,‘ or: is"pu_riiji_ed by suitable operationsjl',v ‘In practice 50
the likeLwhich" can be replaced by or converted; it hasvbeenvfound that satisfactory‘results may bev ‘~ '
_ into CHzCHzOH. Compounds oi’ the ?rst typetq obtained by dissolving about. 23',grams' of crude,
which are termed salts of thiaaole derivatives, may. thio ‘formamide and ‘i6 igramsl'ioitthe vliar-loin aceto
be prepared by condensing a- halogen ketonic‘ a propyl alcohol in 30 cubic centimeters oi absolute
55 compound of the type CHaCOCHXR, in which-X _ alcohol ‘and allowing themiirture to stand £01321. >68
'
hours ata‘room temperature. The resulting prod
the nitrogen atom in one ofthe above described
thiazole compounds and thereby produce a prod
uct analogous to the ,antineuritic vitamin in
which the 'pyrimidine and thiazole nuclei are in
‘ uct, an impure thiazole salt having the formula:
'
,
chemical combination.
'
'
Although in ‘the specific embodiment of the in
vention which has been described, a brom aceto
,propyl alcohol is the halogen derivative employed,
other similar‘ha'logen compounds may be used.
is soluble in water butinsoluble in ethera :After“ For. example,‘ the corresponding chlor aceto
10
the mixture has stood the required‘glength' of 'propyl alcohol, 3 chlor 3 aceto propan 1701, may
time, 100 cc. of water and 200cc. ofi'ether are "be caused to react with thio formamide to pro
added and the material allowed to stand where - duce
upon the mixture separates into two layers, the 1
c'n,
15
15 lower layer comprising an impure water'solution
In a »
=c-0Hmmon
of the thiazole salt and the upper‘ layer compris
ing impure ether. The lower‘ layer is separated
from the ethereal layer and the thiazole salt‘ con
'
tained therein is removed therefrom byany suit-able operations such as arel'weli known inthe art. -.
A satisfactory method of obtaining a pureprod
-
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,
-
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‘ =which corresponds'to the thiazole salt containing
uct from the‘water solution of the thiazole salt
20
brominejpreviously described. The chlor aceto
comprises adding an alkali,’ such assodium'hy ' propyl alcohol employed in this reaction may be
by direct chlorination of the aceto propyi '
droxide, to the water‘ solution 'tonliberatethe 7 made
alcohol.- The 3‘brom 'and_3 chlor derivatives of. 25
thiazole derivative from its combinationwith hy
3 aceto‘ propan 1' 01 ‘may also be prepared'by
drobromic acid. The alkaline liquid is then re
hydrolizing
the‘ a brom and a'ychlor derivatives
peatedly extracted with ether. which extracts the of-a “acetobutyro-lactone.‘
In this connection,
free thiazole'derivative, and-‘the ethereal solu
tion comprising the several extracts is dried over see Jour. Amer. Chem. Soc., voi.‘5,8>, ‘p. 1803 .(l936) .
a dehydrating agent, such as anhydrous sodium This invention also contemplates the vproduction 30
sulphate, after which the ether is distilled off. ~ of thiazole compounds . containing _, iodine = from
The remaining oil is distilled in vacuo and the
distillate collected. - Thedistillate, a clear, vis
cous oil having-a faint basic-odor and boiling at
100° C. under a pressure 0! about‘ limm. of
mercury, is 4-methyl 5~(p-hydroxy ethyl) thia
zole, .which has the graphic formula: .
the corresponding: halogen lretonic compound
containing iodine.‘ The 3 iodo'derivative of 3_
adaptations ' of '1 the methods or ‘I' preparing , the
bromine'and iodine derivatives referred to'here
inabove;
'
'
aceto propan 1 01 maybe preparedby suitable
'
'
as '
‘
The inventioniembraces the production of thi-'
azole compounds" by condensing compounds ,of'the‘
general type CI-IsCOCHXR, in ‘which X is a halo 40'
gen andR~may be the group ‘CHzCHiOI-I. or- a
group which may be converted into or replaced
by I Cl-‘iz‘CHzOI-I, 'withfcompounds of “the type
'ZCSNI-lz,‘ in which Z is hydrogen, anamino group,
a sulfhydryl or other group which may be readily
About 3
of this thiazole _' derivative are
45
produced when the-above mentioned quantities of ' converted'into or "replaced by hydrogen, . The
'brom aceto propyl alcohol and thio formamide
are employed. 'When the material is to be made
in quantities, it will be obvious that larger
amounts of these ingredients should be used.
This material forms addition products with
acids, such as hydrohalic acids,'in"which the'acids
are added'directly to the nitrogen of the thiazole .
nucleus to form pentavalentnitrogen compounds,
which are termed salts. Thesesalts have the
general formula:
.
.
. H
C3!
I‘
‘
‘
,
‘
U
f
.
va=c-cmcn,orr
\
x/ '\'c'->
kind’ of reaction which occurs when _.R is‘
CHzCHzOH and ‘Z is hydrogen has already been
described, _>By analogous reactions related com
pounds, in ‘which R. represents a group, such as
CHaCOOH, CHzCI-IQ, CHzCOOCzHs, ,o‘rnthe'llike,
50
and Z is an amino or a sulfhydryl ‘group,_may' be
prepared. ~Ii! desired, these compounds maybe _
converted into ‘derivatives 'in. vwhich vR?ris
CHzCHzOH and Z-is hydrogen‘ by suitable reac
tions well known in the art. For example, the 55.
groups Cl-hCOOI-I, CHzCHO and CHgCOOCzHs,
‘may be converted into CHzCHzOH by reduction.
An‘ amino group may be converted into hydrogen ‘ I‘
by treatment with nitrousacid, and a sulfhydryl
.
where X is any acid" radical- or a halogen.‘ >When
picrolonic acid: dissolved ini-mlethyl alcohol is
65 added to a water solution of oneof these thiazole
group may similarly be converted or replaced by
the action of an oxidizing agent,such as nitric
acid or hydrogen peroxide.
' It willof course‘, be understood‘ that ‘other ‘
solvents and reagents may be employed to assist
in} ‘carrying out the reactions and to purify the
salts,,a characteristic crystalline/picrolonate re products obtained. ' Furthermore, it may be nec
sults’which, decomposes on heating to 184?- C.‘ essary, to vary the relative proportions of the
The salts ofthese thiazole compounds are crystal
ingredientsathe time‘and/or temperature. of the,
line materials-that arev usually soluble in water _ reactions in“ accordance‘ with the particular de-.
70 but insoluble in ether, and form valuable inter-_ rivativev which is to be produced. These varia 70
mediate productsfor the production of the anti- _ tions are such as are'clearly understood by those
’ neuritic vitamin, orPsimilar’ compounds-
.
'
‘By suitablereactions a pyrimidine derivative,
or a compound capable of being converted into
such a derivative, may be caused to ailix itself to
familiar with the art.
vWhat is claimed is:-
_
"
» a
‘
l. The method of making thiazole compounds
which comprises condensing thio formamide with 76
2,188,969
,
3.
a compound having the formula, CHaCOCI-IXR,
in which X represents a halogen oi’ the group ‘which comprises condensing} chlor 3 aceto pro
l
consisting of bromine, chlorine and iodine and pan 1 01 with thio formamide.
5. The method of making‘ thiazole compounds
R is one of the groups CH2CH2OH, CHzCOOH,
which comprises condensing a compound having,
CHzCHO and CHzCOOCzHs.
2. The method of making thiazole compounds,
which comprises condensing a compound having
the formula CHaCOCHXR, in which X represents
a halogen of the. group consisting of bromine,
10 chlorine and iodine and R is one 01' the groups
the formula CHaCOCHXCHaCHzOH, in which X‘
represents a halogen of the group consisting of .
bromine, iodineland chlorine, with thio torm
nmide.
'
'
6. The method oi.’ making thiazole compounds .
which comprises condensing a. compound having 10
CHzCHzOH, CHzCOOH, CHzCHO and
the
formula CHaCOCI-IXCHzCI-IzOH, in which X '
CHaCOOCzHs
with thio formamide, and treating the resultingv represents a. halogen of the group consisting of ‘
iodine, bromine or chlorine, with thio Iormamide ,
. and treating the resulting product with anvalkali.
7. The method of making thinzole compounds
3. The method voi making thiazole compounds,
compound to convert the group represented by B
into CHaCHzOH.
_
'
which comprises condensing 3 brom 3 aceto pro
pan l 01 with thio iormamide.
4. The method 0! making thiazole compounds,
which comprises condensing 3 iodo ,3' aceto pro
pen 1 01 with thio tormamide.
,
nnwm a. poem.
‘
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