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GOVERNMENT OF INI>IA: THE PATENT OFFICE, 214, LOWER. CIRCULAR ROAD, CALCUTTA-17.
Specification No. 62890. Application No. 62890, dated 20th January 1953. CompleteSpecification left on 15th October 1958,. (Application accepted 15th July 1959.)
PROVISIONAL SPECIFICATION.
A NEW PROCESS FOR THE PRODUCTION OF 4-HYDROXYCOUMARIN AND ITSDERIVATIVES.
COUNCIL OF S CIENTIFIC AND INDUSTRIAL RESEARCH, OLD MILL R OAD, NEW DELHI-}. INOlA, AN INDIAN
REGISTERED .!lODY INCORPORAIED UNDER THE REGISTRATION OF SI)cIETIES Acr (ACT XXI vF 1860).
The following specification describes the nature of this invention.THIS IS AN INVENTION BY VINOD RAMANLAL SHAH, JOGENDRA LAL nOSE AND RAMANLAL CHHAGANLAL
SHAH, OF TIlE DIVISION OF ORGANIC CHEMISTR't OF THE NATIONAL CHEMICAL .CABORATOJ
15 parts by volume of POCI, (=25'1 parts) and 15 parts of
anhydrous zinc chloride arc heated III 75-110 with stirring for4 bOlles_ The reaction mixture is worked up in the same way
as in Example 1, the resuiting crude 7-methyl 4-hydroxycou-
mBrin being finally erystallised from glacial acetic acid m.p.219-20.
EXAMPLE 5.
254 Parts of phenol, 5'84 parts of octYl-malonic acid with
75 plrtS by volume of POC1, (=126 parts) and 8 parts of"
anhydrous zinc: chloride are heated at 70-75 with stirring for
10 hours and then decomposed wit~ ice and water. The mix-
ture is heated a little in the waterbath, cooled and filtered
under suction_ FirRt purification may be done by dissolving
in c~"'tic soda and precipitation with HCL On crystallisation
from slighi!y diluted alcohol puf'e 3-n-octyl-4-hydroxycouma-
rin is obtained in colourless plates, m.p. '145:.
The foUowing compounds can be produced according to
the methods described in the above examples.
8-methyl-4-hydroxycoumarin, m.l'. 231-32'
6-rnethyl-4-hydroxycoumario, m.p. 252-53"
5-methyl-8-isopropyl-4-hydroxycoumarin, m.p. 222-25"
4-hydroxy-5: 6-benzocoumadn, m.p. 278-79'
4-hydroxy-7: 8-benzocoumatill, lII.p. 284-85
5: 8-dimethyl-4-hydroxycoumarin, m.p. 261-62
3-n-propyl-4-hydroxycouma,in, m.p. 139-40'
3-n-buty.l-4-hyuroxycoumarin, m.p. 159-60
3-n-hexyl-4-hydroxycoumari:n, m.p_ 154-55
3-phenyl-4-hYdroxyeoumarin, m.p. 229
SUMMARY.
The invemed process fOT the production of 4-hy"roxy-
coumarins with or without alkyl substituents in the ortho
arylene part of the molecule and/or an alkyl or aryl SUbsti-
tuent in the 3"position is characterised by allOWingthe reac?on
between an alcomatic hydroxy compound and free or an alkyl
or aryl substituted malonit acid to take place between 0-110
in the presence of phospbQn.ls o,{ychloride and anhydrouslUn" chlorid~.
" " - "
R. BliASKAR PAl,
Patents Officer,
Council of Scientific & Industrial Research.
Dated this ~rSth day of January 19S8,
P~ic'e: -rWQ RVPEII'S.
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COMPLETE SPECIFICATION.
62890
A NEW ]PROCESS FOR THE PRODUCTION OF 4-HYDROXYCOUMARIN AND ITSDERIVATIVES.
COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH, OLD MILL ROAD, NEW DELHI-I, INDIA, AN INDIAN
REGISTERED BODY INCORPORATEDUNDER THE REGISTRATION OF SOCIETIES ACT (ACT XXI OF 1860).
The following specification particularly describes and ascertuins the nature of this invention and
the manner in which it is to be performed.
THIS IS AN INVENTION BY VINOD RAMANLAL SHAH, JOGENDRA LAL BOSE AND RAMANLAL CHHAGANLAL
SHAll, OF THE DIVISION OF ORGANIC CHEMISTRY OF THE NATIONAL CHEMICAL LABORATORY, POONA, INDIA, ALL ARE
INDIAN CITIZENS.
The present invention relates to a new process for the pro-
duction of 4-hydroxycoumarins, of J-substitutcd 4-hydroxy-
coumarins as well as analogues modified in respect of the aro-.
matie ring and of I-thio-analogues of these compounds.
4-Hydroxycoumarin is a valuable intermediate for the pro-
duction of importanl anticoagulant drugs such as 3: 3' -methy-
lene-bis-4-hydroxycoumarin and bis-[4-hydroxycoumarinyl-(3)]-
acetic acid ethyl esler and also for Ihe production of important
useful rodenticides such as 3-(a-phenyI-,B-acetyl ethyJ)-4-hydro-
xycoumarin.
Of the previously known methods for the preparalion of
4-hydroxycournarin, the following may be mentioned in parli
cular :
(I) Heating acetylmethyl salicylate with an alkali metal
or its alcoholate or alkali metal amide in the pre-
sence of a high boiling hydrocarbon as the reactlon
rnediurn.
(2) Condensation of acetyl salicyloyl chlo;:ide with aceto-acetic, cyanacetie or malonic esters and conversion
of the resulting 3substitllted-4-hydroxycollmarins
to 4-hydroxycournarin.
(3) Condensation of o-hydroxyacetophcnone with diethyl
carbonate in tht: presence of an alkali metal or its
alcoholate or hydride, and
(4) Heating diphenyl malonate with anhydrous aluminium
chloride to about 180" C.
The prodllction of 4-hydroxycoumarin hy the Ilrst three of
the above methods is relatively costly, particularly for the
nuclear substituted 4-hydroxycoumarins as most of the start-
ing materials, namely, substi~uted salicylic acids and substituted
o-hydroxyacctophenones arc not easily available.
A novel and surprisingly simple method has now been dis-
covered by us by which 4-hydroxycoumarin. 3-substituted-4-
hydroxyc0umar~ns as well as their analogues filodified in res~
peet of the aromatic ring and thio- analogues of these com-
pounds as represciltcd by Formula I in the accompanyingdrawjngs, wher:.::Ar denotes an urtho-arylenc radical whk:h
can be slibstituted by alkyl groups and R denotes hydrogen or
an alkyl or an aryl radical and X denotes oxygen or sulphur,--
can be p'eparcd in good yields if aromatic hydroxy or me['-
canto COQ1Pounds h:O:lving at least one ortho position free as
represent."i by Formula Il,where Ar has the same meaning as
in Formula 1 is leaded with a malonic acid CIS represented by
the general Formula lIT. where R has the same meaning as in
Formula t in lhe presence of a nlixture of phosphorus ox:y-chloride and anhydrous zinc chloride at temperatures ranging
from 30 to 1100 C,
The invented proces,; for the production of 4-hydroxy-
coumarins of Ihe general Formula I of the accompanying draw-
ing:, where Ar d'.,notes an orthoarylene radical which may be
subslitut"G by ~,Ikyl. groups and R .denotes hydrogen. or ,-,lkyl
or an aIyl radical and X denotes oxygen or sulphur, is charac-
terised hy allo~ling the reaction between an aromatic hydroxy
or thio comnourld having at least one ortho position free as
represented by Formula ][1 where Ar has the same meariing as
in Formula I and a malonic acid as represented by Formula
1fT or its lower alk'll ester where R has the same meaning as
in Formula I, to t~ke place by heating them together with a
mixture of phosphorus oxyehlvride and anhydrous zinc chlo--
ride at temperatures between 30" to 110" C.
Inert liquids like liquid paraffin may be used in the r,eac-
tion as a thinner and heat transfer medium, Lower alkyl
esters of malonic acid may also be used in this reaction in the'
pbce of malonic acid or 3-suhstituted malonic acids respec-
tively. but the yields of the final product are usually poor.
Wh"n the reaction is carried out with phenol and malonic
add, yields upl.o 60 per cent. of theoretical of a fairly !'ure
quality of 4-hydroxycoumarin. having m.p. 204-6" can be
easily ob'ained in one single stage, The sequenec of addition
of the reactants or the condensing agents in the newly di8-
,covered method may be varied in any suitable manner desired,
Thus a mixture of phosphorus oxychloride and anhydrous zinc
chloride may Ilrst be stirred with or without heating followed
by addition of the reactants and heating with stirring as usual.
There is still scope [or improving the yields further by intro-
ducing ehanges in the expeTimental conditions. More'over, a
substantial portion of un reacted malonic acid can be recovered
from the aqueous acidic liqui
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resulting pasty solid is !tered, washed and macerated with ether
a;d .t hen w it h 1 0 per cen t. s od iu m carbo nate s ol ut io n. T he
sodium carbonate extract is separated from the mixture freed
of dissolved ether heating on the water bath, ceoled, filtered
and 4-hydroxycoumarin precipitated with hydrochloric acid.
On crystallisation from water ur dilute alcohol pure 4 hydroxy-
coumarin, m.p. 209-10' is obtaincd.
EXAMPLE 4.
4-HydToxycollmarin.
10.7 Parts of phcnol, 11'85 parts of malonic acid 32 parts
by volume oE phosphoms oxychloride 492 parts of anhydrousL in c chl orid c and 1 6 parl ' b y v ol ume o f l iq ui d p aral ti n are
healed with stirring at 60-65" [or 27 hours. The reaction mix-
ture is coukd and decomposed over ice and water. The solid
separating out is filtered and washed with water and then with
petroleum ether (b.p. 60'-80" C.). T he s ol id i s pu ri fi ed b y
dissolving in hot 5 per cent. sodium bicarbonate solution,
filtration and acidification with hydrochloric acid. The yield
i s 9 '0 7 p arts m.p . 2 04 -7 ' (42 2 p er een l.). Cry st al li sati on
from water gives pure 4- coumarin, m.p. 209-10".
EXAMPLE 5.
7 -M ethyJ-4-hydroxycollmarin-
5 -4 Part s o f m-cr~so l and 5 2 p arts o f mal on ic aci d arc
beateu at 70-75' with 14 parts by volume of phosphorus oxy-
chloride and 13'6 narts of anhyarous zinc chloride with stir-
ring for 12 hours -'-The reaction mixtur~ is cooled and decom-
posed with ice and water and ldt standing [or sonletime. The
resLllting solid is dissolved in 10 per cent. sodium bicarbcnate
~olution in hot and filtered from the insoluble impurities.
7_'-1ethyl-4-hydroxycoumarin is precipitated from the filtrate
with hvdrochloric acid. Yield is 5'72 parts (65 per cent.). On
crvstallisation from glacial acetic acid, the pure coumarin,
m:p. 222-23' is obtained.
EXAMPLE 6.
4-Hydroxy- 5:6-oenzocD umarin.
7.2 Parts of .S-naphthol and 52 parts of malonic acid are
heated at 70-75 with 18 parts by volume of phosphorus oxy-
chloride and 26 parts of anhydrous zinc chloride with stirring
for 9 hours. After cooling, the reactinn mixture is decomposed
w it h i cean u w at er and all ow ed 1 0 s tand for so nl et ime. T he
resulting saEu is ftlter~d under suctiOIl~ washed and dissolv~d
in 10 ~er cent. sodimn bicarbonate solution, filtered and 4-
hydroxy-5: ('-benzocouma,in precipitated with hydrochloric
acid. Yield is 98 paTts (92'4 per cenl.). Crystallisutioll fromalcohol gave the pure coumarin, m.p. 278-79".
EXA~rPLE 7.
4- Hydroxy- 5-mcth)'i-S-i
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COMPLETE SPEClFICAT,oN
COUNCIL OF SCIENTIFIC
AND
INDUSTRIAL RESEARCH
NO. {,2. Bj '?o ~
I
IT
ill
No OF SHEETS
SHEET No I .
t~r -X ~--H
/ ...COOH
R-CH
' ..eaOH
R. B. PAl,
PATENTS' OFFICER,
C.S.I.R