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Патент USA US2404416

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Patented July 23, "1946
‘ 2,404,416
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
The ap-dihalogeno monocarboxylic esters of a
This invention relates to a process for pre
paring 4-substituted thiazoles.
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
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
to. provide a new process. for preparing 4-substi- ,.
tuted: thiazoles.
p ’
Other objects will become ap- ~
parent hereinafter.
In accordance with my invention,'I prepare
4-substituted thiazoles by condensing a thioamide
containing the
88 g..('0.51' moi.) of‘ m?édichloroisopropylvace
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
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;
, 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
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.
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,
19, 10 (1939) ‘and references
on thelother
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).
Example ‘2.1-2eamino-st-rnethylthiazoleI
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:
. obtained
and condensing
by addingwith
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
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
‘2. A process ‘for preparing] a‘ 4-s'ubstituted thi
Example 3.;u,c-dib§romoisopropyl acetate ' >
azole comprising condensing 'a thioamide con
taining the '—CS,-,-NH2 group‘, with aJS-‘dichIQro
. 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
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
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
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'. .
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
each case. f'
In’a ‘manner similar'to that shown inEXamp'Ies- ‘
,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
.-1'1v2.,A processifor' preparing‘,2,4-dimetliyithi¥' A
70 '
azole comprisingv condensing,‘ in an .aq'ueou's‘medie
‘ um‘). thioacetamidey-with mpedibromoisopropyl
’ _
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