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Патент USA US2404416

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Patented July 23, "1946
‘ 2,404,416
UNITED ‘STATES PATENT bF'FilCEi.
2,404,416
‘ ' PROCESS Fort PREPARING 4-SUBSTITUTED
~
,
~
THIAZOLES
.
William. P. Utermohlen, Jr., Kingsport, Tenn, as
signor- to Eastman Kodak Company, Rochester,
N. Y., a corporation of New Jersey
No Drawing. Application June 9., 1945,
. '
'
Serial No. 598,637.
' 12 Claims.-
' 2
1
The ap-dihalogeno monocarboxylic esters of a
This invention relates to a process for pre
paring 4-substituted thiazoles.
V
_
the ‘above general formula can be prepared by
chlorinating or. brominating unsaturated esters,
such as isopropenyl acetate (z-acetoxypropene
,
It. is known that 2,-amino-4-methylthiazole
can. be prepared by condensing, thiourea with
chloroacetone. In United Statesv Patent. 2,242,237, .
1)., 2-acetoxy-hexene-l, 2-_acetoxyheptene'-1, 2
’(chlorozrcetoxy) -hexene'-1,, 2 - benzoyloxyhexene- -
dated May 20, 1941, the preparation of 2-amino
1, ya-acet'oxystyrene, 2- (phenylacetoxy) -propene
thiazole from thiourea and‘ 0:,B-di0hl0l‘08th3'l ace
tate. or a,p.-dibromoethyl. acetate is described.
This patent. also discloses the. formation-poi 2
4
._
1, 2-acetoxy-3éphenylpropene-1‘, etc.
Such un
‘ saturated esters in which the acid radical is an
10 ‘acetate radical (i. e. the acetoxy derivatives) can
amino-4-methylthiazole from thiourea ; and 00,13
dichloropropyl acetate.
‘
(01. 260--302)
be prepared by condensing an appropriate ketone
, ,
with ketene, in. the presence of sulfuric acid. See
I have now' found that thiourea and oLNB-(il
Gwynn and Degering, Journalof the American
ChemicalSociety 64, 2216' (1942). All the un
chloroisopropyl acetate. condense to give 2-amino
4-methylthiazole, a wholly unexpected end-prod
uct,1'in view 'of the prior reported, condensation
with m?-d-ichloropropyl. acetate. If the cap-di
chloropropyl acetate gives the‘ é-methyl deriva_
saturated‘ esters can beprepared by. adding a ,
monoécarboxylic acid to the appropriate mono
substitutediacetylene, in the presence of boron
tri?uoride. See Hennion and Nieuwland, Journal
tive, it would be expected that the cc?-CiiChlOl‘O
of the American Chemical Societybfi, 1802 (1934).
isopropy-l- acetate would’ give the B-methyl, deriv
The following examples will serve to illustrate
atives. Not only have I, been able to prepare. 20 further the manner of practicing my‘ invention.
2i-amino-4emethylthiazole, but valso other 4-sub
stituted thiazoles ‘using either ¢,p-dichloro or 11,}?
dibromo monocarboxylic esters with: other thio
amides containing the --CS—-NH2. group. g
.
It. is,v accordingly, an, object of my invention
‘2'5
to. provide a new process. for preparing 4-substi- ,.
tuted: thiazoles.
'
p ’
Other objects will become ap- ~
parent hereinafter.
'
,p
In accordance with my invention,'I prepare
4-substituted thiazoles by condensing a thioamide
containing the
88 g..('0.51' moi.) of‘ m?édichloroisopropylvace
30
group with an 0;,?-di
tate were added dropwise, with stirring, to a solu- , ,
halogeno monocarboxylic ester 'of the following
general formula:
“
'
-
tion of thiourea (4,6.4i1g.,}0.61 mol.) in water (100
ml.) heated to 100° C. The, reaction mixture was
maintained at 100° C., with stirring, for about 3
.
hoursi The resulting solution was cooled to 10
wherein X represents chlorine or bromine and R
and-R" each represents, an alkyl group,_ an aralkyl
group or an aryl group.‘*Thefcondensationsare
advantageously effected in
aqueous-medium;
Heat accelerates the icondensationsv ‘Following
R1150' C. and made strongly‘ alkaline with a'co‘ne
centrated aqueous ‘solution of sodium hydroxide.
‘The upper‘ dark oily layer which separated was
‘separated-off, andthe'aqueousilayer was extract;
40
, ed'withis'ever'al portions (about zoomrsin all) of "1
benzene. '
The ‘dark oil ‘and’ the benzene "extract
were‘ combined'and' partially-dried over solidtsoe
the condensation, the reaction‘ mixture is-made
dium hydroxide. The sodium hydroxide was, 111-‘ v'
alkaline.‘ with a- base which. is stronger thanthe 45 tered' off and they ?ltrate ,fractionallyfdistilled in
vacuo. After the benzene forerun, ‘the '2-amino
é-substituted thiazole, in: order to. free the. 4-sub
stituted thiazole from its hydrochloride: or hydro
4-methy1thi'azole distilled‘ over as a‘ yellow 'oil
which ‘became a‘solid' vupon standing. The 2;
bromide. , Alkalimetal hydroxides, eyg. sodium or
potassium hydroxide, "are advantageously em
ployed.
.
.
From thiourea, 2-amino.-4—substituted thiazoles
can‘ be prepared, from thioacet'amide, ‘2-methyl
lt-substitute'd thiazoles can bev prepared, from thi_
ophenylacetamlde, 2-benzyl-4-substituted thia
‘zole's can be prepared, from ‘thiobenzamide, 2
phenyli-‘i-substituted thiazoles" ‘can: be prepared,
amino-4-intethylthiazole boiled at 103° C. at‘ 1
to mm. of Hg. pressure. {Theyieldwas 4'7 g._ (80 per
cent) based on the u,,8'-dichloroisopropyl' acetate
The product melted atv 44 to 45f’ C. and an acetyl derivative prepared therefrom. ‘melted ‘at; 131,110 - , '
- 132;?’ C.
55
These melting-‘point .valuesyagreefwell ‘
with‘ those previously, reported forgz-aminoélle '
etc.‘ When R represents methyl, a1 4-methylthia
zole is obtained, when R. represents ethyl, aa4z-ethe
methylthiazole and its‘ acetyl derivative . (s‘eeQrg,
Syn.
2-amino-S-methylthiazole,
19, 10 (1939) ‘and references
on thelother
thereinhand,
ylthiazole isobtalned, when R; represents benzyl,
~melts at 95 to 965° C'. and its acetyl derivative
a 4-benzylthiazole is obtained, when R represents
phenyl, a ‘ll-phenylthiazole is obtained, etc. ,
melts at 224° C. ' See chem. lAbSt. 35, 458 (1941).
‘2,404,416
Example ‘2.1-2eamino-st-rnethylthiazoleI
l
V ,3_ and 4,12-acetoxyhexene-i1.‘ 2-acetoxyheptene-1,
133 g. (0.51 mol'.) of a,p-dibromoisopropyl ace
2 - (chloroacetoxy') - hexeneé 1, 5-2 e-ben‘zoyloxynex
tate were condensed with thiourea exactly as in
ene-l, u-acetoxystyrene, 2-(phenylacetoxy) - pro
Example. 1. The yield of 2-amino-4-methy1
- p'ene-l, 2-acetoxy-3-phenylpropene-1, etc. can be
thiazole was ‘54.5 g. (93 per cent) based on the’ I chlorinated- or brominated to give dichloro or di
mp-dibromoisopropyl acetate.
v‘ -
bromo saturated ‘esters.
‘
What I claim as my invention and desire to be 4 V
Using thioacetamide instead of thiourea, and
proceeding'exactly as’ in Example 1, a good'yield .
secured by Letters Patent of the United States is:
of 2,4-,dimethylthiazole can be obtained; with‘
‘1. A process for preparing a 4-‘substituted thi
thiobenzamide, 2-phenyl-4-methylthiazole ‘can be 10 azole comprising condensing a thioamide con
obtained, with thiophenylacetamide, 2-be'nzyl-4- " taining, the —__--CS—NH2 group with adihalogeno
methylthiazole can be obtained, etc. Using? the ‘ ester of the following general formula:
dichloroester
u-acetoxystyrene
. obtained
and condensing
by addingwith
chlorine
thiourea,
;,to
2-amino-4-phenylthiazole can be obtained, using 16
the dichloroester obtained by adding chlorine to
qracetoxystyrene and condensing withthioacet- '
amide;2emethyl-4-phenylthiazo1e can be ob
tained,
etc.
7
j
.
‘
i
‘
‘
_
20
The following examples illustrate further the
preparation ofthe dichloro and dibromoesters.
wherein R and R1 each represents a'n'i'embe'ri'sa.
lected from the group consisting of alkyl, aralkyl
and aryl'gr'oup's and‘X'represents- a halogen se
lected from the‘ group’ consisting of chlorine and
bromine.
'
'
i
*7
‘2. A process ‘for preparing] a‘ 4-s'ubstituted thi
Example 3.;u,c-dib§romoisopropyl acetate ' >
25
azole comprising condensing 'a thioamide con
taining the '—CS,-,-NH2 group‘, with aJS-‘dichIQro
isopropyl
acetate.
'
'
'
'
--
»
. 3. A process for preparing a 4-substitut'ed thie
'azole comprising condensing-a thioamide con‘
‘300 ‘g; ('3’mo1.) .of isopropenyl acetatewere
taining the —CS’—NHI2 group withjap-dibromo
stirred andcooléd to 0° C. 7450 ‘g, v(2.8+ mol.) of
r
bromine ‘were directly added, dropwise, maintain 80' ‘isop'ropyl acetate. g =
_ 4. A process for preparing ‘2-amin'o-4imethyli
ing the temperature at 0° C. The'bromine' was ,
thiazole‘ comprising" cond'ensing» thio'ur'ea with ,
immediately taken up. After addition ' of the
0a,,3gdi0hlOI‘OiS0IJI‘ODY1 acetate} '
bromine,‘the reaction mixture was fractionating
5. A process for preparing 2-amino‘-4j-methyli
in 'va‘cuo,,using ‘a total-condensation, variable,
takeoff still. Hydrogen bromide-and’ unchanged
isopropenyl acetate were the ?rst fractions to be
comprising" condensing thio‘ur'eaiwith' ’
35 thiazole
a,B-dibroinoisopropylacetate;"
'
r
_.
.
4
f 6. A process for preparing'2,4edimethylthiazole
distilled. _The q,;8-dibromoisopropyl acetate was,
. comprising condensing tliio cetami'de with-‘bi
next obtained,‘ andahigh boiling, residue was left
behind. The e,p-dibromoisopropyl acetate boiled
at 62 ‘to 635° C. at 40 mm. of Hg. pressure. It 40
was a mobile liquid, colorless :when freshly dis-V '
tilled and was'a strong lachrymator. N20/D
1.4714; D 20/20 1.6249. Bromine, calculated 61.5
per cent, found 61.8 per cent.
withla‘idihalogenofester of the ‘fqnqwmgjeene 1
-
M, Example 4.—cz,;3-diChlOT0iSOZPTOZJ2/l ‘acetate
wherein R and R1 each represents am
er sci
50‘ lected from the'grou'p consisting of alkyl, ara kyl
' ‘300g.’ (3' mol.); of isopropenyl acetate 4 were
and aryl groups andKrsPl?SenE a. halogen se
lected from the group consisting of chlorine and
- stirred and coo1ed~to;0°' C. Chlorine gas was,
passed intothe cold'isopropenyl acetateqmainev
'
' taining: the temperature {at 0° 0., until somewhat
bromine.
‘
8. YA process.v for preparing:v a'.4esubstituted:thi
more~than3 moles of chlorine-wereadded, _Ni
azole, comprising condensing-yin, anaqueous medi*
trogen gas was then blown throughthe reaction‘, 55 um, a thioamide containing; the -'-.-CS?NH2 group
mixture :to sweep out anyremaining free chlo-:
with a?edichloroisopropylacetate.. - rine; The -.-'mixture was then _'fractionated .in; - .9.» Aprocessforpreparingra 4-_s_ubstituted_thif
3 . vacuo as in Example 3, I-Iydrogenchlo?ddun-I
azole comprising condensingfin anfaqueousm‘edF ‘
1 reacted isopropenyl- acetate, ap-dichloroisopropyl
um, a thioamide containing the I—CS NHz ‘group
‘ acetate ‘and a high boiling residue was obtained‘.v 60 with ap-dibromoisopropsll ac'etate'. .
1r.
The ,a,,c-dichloroisopropyl acetate boiled at , 45 , to
'- "10; A' process for preparing-zzeamino, . methyl
46? C.- at 41 mm. of 'Hg. pressure. , It was afmo
thiazole. comprising .conde'nsing,‘ in’ian aqueous '
bile liquid,‘ colorless when freshlydistilled, and
was a ’ lachrymator. ,
medium; thiourea with.a,p-dichloroi-sopropyl ace?~
N _20/D 1.4344; . D 20/20‘ 65
1 *1.2158. Chlorine, calculated 41.5 percent, found
eujciper cent. In this exampleand injE'xample 3.,
=. dp-dihalogenoisopropyl acetate were of. the order ‘
‘erable'unreacted isopropenyl acetate was; récovi
cred
each case. f'
In’a ‘manner similar'to that shown inEXamp'Ies- ‘
I
,
4
,1; I‘ ‘f
11.; A process for preparing‘2gaminoe4emethyl
thiazole comprising condensing; in an: {aqueous
medium, thiourea with a-p-dibromois‘opropyl‘ace
the.‘ conversions, of isopropenyl acetate, to'thev
a; "of 40to 59 percent. 'The'yields, based on iso
' ‘1 propenyl acetate, were much higher since'consid
tate.
‘I
'
.‘
1
.
.
.
i
,3‘
,
,
1.
v;
.-1'1v2.,A processifor' preparing‘,2,4-dimetliyithi¥' A
70 '
azole comprisingv condensing,‘ in an .aq'ueou's‘medie
‘ um‘). thioacetamidey-with mpedibromoisopropyl
acetate;
’ _
,
..
WILLIAM. P._~'U'I'ERMOI-IILEN JR
»
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