Note: Descriptions are shown in the official language in which they were submitted.
1151~i~8
This application is a division of application Serial No. 356,356,
filed on July 16, 1980.
This invention relates to a novel process for producing 7-alkoxycar-
bonyl-6,8-dimethyl-l-phthalazone-4-~-hydroxyacetic acid, an intermediate com-
pound formed in the process for preparing 7-alkoxycarbonyl-6,8-dimethyl-4-
hydroxymethyl-l-phthalazone disclosed in Canadian patent Application Serial No.
356,356.
The invention also relates to a process for producing 7-alkoxycar-
bonyl-6,8-dimethyl-1-phthalazone-4-a-hydroxyacetic acid represented by the
10following formula (IX):
CH(OH)COOII
~ (IX)
RlOOC ~ \ ~ NH
CH3 0
(wherein Rl is a lower alkyl) or a salt thereof, which comprises hydrolyzing
7-alkoxycarbonyl-6,8-dimethyl-4-(a-halogeno-a-substituted methyl)-l-phthalazone
represented by the following formula (VI):
CIIX - 1~4
3 ~ `1 ~ N (VI)
RlOOC ~ ~ \ ~ Nll
CH3
-- 1 --
~,
~lS164~
wherein Rl is as defined abovc, X is a halogen atom and R4 is -CONll2 or -COOH,
with a base.
As a preferred embodiment of the above process, a compound of formula
(IX) is used wherein Rl is -C2H5. A further preferred embodiment is when R4 is
-COOH.
The invention further relates to a compound of formula (IX) as de-
fined above, or a salt thereof, whenever prepared by the above process or by an
obvious chemical equivalent thereof.
7-Alkoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1-phthalazone (herein-
after referred to as 4-hydroxymethyl-1-phthalazone) represented by the follow-
ing formula:
C1120H
3 ~ N (VIII)
RlOOc '~1~
CH3 O
wherein Rl is a lower alkyl, is a compound originally produced by Shimamoto,
Ishikawa et al. through a structure-activity relationship study of a series of
compounds having phthalazone skeleton. Ilaving a very strong inhibitory action
on the coagulation of blood platelets and an inhibitory action on phosphodi-
esterase, this compound is expected as an effective therapeutic medicine for
cerebral hemorrhage, atherosclerosis and cerebralapoplexy (United States Patent
3,963,716; Austrian Patent 7,408,744).
The process mentioned in the above-mentioned patent has a fault
in that mass production of the objective compound is difficult because the
starting compound itself is difficult to synthesize.
For example, in the process for synthesizing 5,7-dimethyl-6-ethoxy-
carbonyl-3-hydroxy-3-methylphthalide (B) by reacting 3J5-dimethyl-4-ethoxycar-
bonylphthalic anhydride (A) with dimethylcadmium as shown in the following
scheme:
EtoCH3 ~ ~ EtOOC
C~13 O CH3 O
(A) (B)
the cadmium is a dangerous heavy metal and the reaction required use of a large
quantity of ether under an anhydrous condition. Thus, the process is undesir-
able as an industrial production process.
In the process for synthesizing the phthalide derivative (B) by re-
acting the above-mentioned phthalic anhydride derivative ~A) with malonic acid
(Japanese Patent Kokai (Laid-Open) ~o. 84~563/1975) a position isomer ~C)
represented by the following formula:
~S~6~
EtO~C ~
CH3
CH3 OH
(C)
is formed as a by-product.
The present inventors have discovered a process suitable for mass
production and having none of the faults mentioned above.
According to the process disclosed herein, the objective compound can
be obtained from an inexpensive starting material in a high yield.
By the process of the inventors 4-hydroxymethyl-1-phthalazone re-
presented by formula (VIII) can be synthesized in the following manner.
4-Hydroxymethyl-l-phthalazone represented by the following formula
CVIII~
Cl'120~1
~ ~ (VIII)
RlOOC /~Ntl
CH3 O
wherein Rl is a lower alkyl, is produced by:
1~51f~
~ A) reacting 3,5-dimethyl-4-alkoxycarbonylphthalic anhydride represented
by the followi.ng formula:
O
CH3
~ ~ C (I)
RlOOC ~{
11
CH3 O
wherein Rl is as defined above, with a compound represented by the following
formula:
~ P = CH - R2 (II)
wherein R2 is -CN or -COOEs (Es is an ester residuc) to obtain 6-alkoxycarbonyl-
5,7-dimethyl-~3'~-substituted methylenephthalide (hereinafter referred to as
methylenephthalide) represented by the following formula:
Cl I - R2
~//~\
ll O (III)
RlOOC
CH3 O
l~S~
wherein Rl and R2 are as defined above, followed by
~ B) reacting the methylenephthalide compound of formula (Ill) with
hydrazine to obtain a compound represented by the following formula:
C~2 R3
C~l ~ H (IV)
CH3 0
wherein Rl is as defined above and R3 is -CN or -CONHNH2,
(C) hydrolyzing the compound of formula ~IV) to obtain 7-alkoxycarbonyl-
6,8-dimethyl-4-substituted methyl-l-phthalazone ~hereinafter referred to as 4-
substituted methyl-l-phthalazone) represented by the following formula:
CH2 ~ R4
~ (V)
RlC ~
CH3 0
wherein Rl is as defined above and R4 is -CONH2 or -COOH,
~ D) halogenating the compound of formula ~V) to obtain 7-alkoxycarbonyl-
6,8-dimethyl-4-~-halogeno-~-substituted methyl)-l-phthalazone [hereinafter
referred to as 4-~-halogeno-~-substituted methyl)-l-phthalazone] represented
by the following formula:
~S~64~
C~IX - R4
CH
~ N ~VI)
RlOOC /~
CH3 O
wherein Rl and R4 are as defined above and X is halogen atom, and then
(E) hydrolyzing and decarboxylating the compound of formu]a (VI) by
either of the following methods (a) and (b):
(a) directly hydrolyzing and decarboxylating the compound of formula (VI),
(b) when R4 is -COOH in the compound of formula (VI), reacting the com-
pound of formula (VI) with a carboxylic acid salt represented by the following
formula:
(R5COO)nM (VII)
wherein R5 is a hydrogen atom, an alkyl, aryl or aralkyl, M is alkali metal or
alkaline earth metal, and n is 1 when M is alkali metal and 2 when M is alkaline
earth metal, and simultaneously decarboxylating the acyloxylated compound and
then hydrolyzing the decarboxylated compound, or firstly decarboxylating the
compound of formula (VI), reacting the product with the carboxylic acid salt
of formula (VII) and then hydrolyzing the reaction product.
(c) when R4 in formula (VI) is -CONH2, reacting the compound of formula
(VI) with the carboxylic acid salt of formula (VII), and then hydrolyzing and
decarboxylating the acyloxylated compound simultaneously.
The characteristic features of this process are that the methylene-
napthalide represented by formula ~III) can be produced in a very high yield by
1~L5164~
reacting 3,5-dimethyl-4-alkoxycarbonylphtllalic cmhydride represented by formula
(I) with the compound represented by formula (II) without forming the unnecessary
position isomer represented by the following formula:
o
~ y
CH3 CH-R2
at all, a series of reactions starting from the methylenephthalide of formula
(III) use quite conventional reaction conditions and are easy to operate, the
starting material is inexpensive and the overall yield is very high.
Most of the intermediates obtained in a series of steps of this
process are novel compounds.
For example, the compound of formula (IV) and the compound of formula
(V) are both novel, and they can be represented generally by the following
formula:
CH-R
~ ~ I
RlOOC ~ NH
Cl-l O
wherein R] is as defined above and R6 is -CN, -CONHN112, -CON112 or -COOH. The
compounds of formula (III) and formula (VI) are also novel.
In the inventors' process the reaction of step (A) between 3,5-
dimethyl-4-alkoxycarbonylphthalic anhydride of formula (I) and the compo~md of
formula ~II) is usually carried out in the prcsence of a solvent and preferably
an organic solvent, usually at a temperature ranging from 0C to the boiling
point of the solvent and preferably from 0C to about 50C. The reaction can
usually be completed in a reaction time of 2-4 hours. Though the solvent used
is not particularly limited so long as it is inert to the reaction, examples of
-- 8 --
l~S~6918
the preferable solvent include aromatic hydrocarbons such as benzene, toluene
and xylene, halogcnated hydrocarbons such as methylene chloride, chloroform
and carbon tetrachloride, and ethers such as ethyl ether, isopropyl ether,
tetrahydrofuran and dioxane.
The reaction is carried out by using the compound of formula (II)
in an amount of 0.5 to 2.0 moles per l mole of 3,5-dimethyl-4-alkoxycarbonyl-
phthalic anhydride of formula (I). Preferably, the inexpensive compound of
formula (II) is used in an amount of l.0-l.3 moles per l mo]e of the latter.
The methylenephthalide of formula (III) obtained by this reaction is a
5-7 : l mixture of the geometric isomers (III') and (III") shown below:
11 ~ R2 R2 ~ I I
3~ // ~ CH3 ~
Rl OOC I Rl OOC
CH3 0 CH3 0
~III') (III")
Since these geometric isomers given the same compound of formula (IV) when
reacted with hydrazine in the subsequent step, it is unnecessary to separate
them from each other. Further, the triphenylphosphine oxide formed in this
reaction has no harmful effect in the subsequent reaction. Therefore, the
liquid reaction mixture itself or the residue obtained by distilling off the
solvent therefrom can be used as a crude product in the subsequent reaction.
When isolation of the product (III) is necessary, column chromatography using
a silica gel is most suitable. It is also possible to isolate the product (III')
either directly from the reaction mixture or by recrystallization of the crude
product because, among the geometric isomers, the isomer (III') has a lower
solubility in aromatic hydrocarbon solvents than the other isomer (III").
Many of the 3,5-dimethyl-~-alkoxycarbonylphthalic anhydride re-
presented by formula (I) are known compounds. Eor example, some of them can
be obtained easily by condensing an alkyl ester of isodehydroacetic acid with
a diester of acetylenedicarboxylic acid to produce a phthalic diester deri-
vative, saponifying the latter and then treating the saponified product with
acetic anhydride.
The lower alkyl of Rl in formula (I) can be, for example, methyl,
ethyl, propyl, butyl, pentyl and hexyl. These are not limited to a straight
chain form, but may be branched if possible. Halogen atoms of X in formula (VI)
are chlorine, bromine, iodine, ar.d fluorine.
R2 of formula (II) is -CN or -COOEs (Es is an ester residue) and
examples of -COOEs include lower alkoxy(ClC6)-carbonyls such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl; aralkoxycarbonyls such as
benzyloxycarbonyl, phenylethyloxycarbonyl, chlorophenylpropoxycarbonyl; aryl-
oxycarbonyls such as phenoxycarbonyl and substituted phenoxycarbonyls. Usually,
the compound of formula (II) can be obtained by reacting triphenylphosphine
with bromacetic ester or bromacetonitrile and most of them are disclosed
compounds.
In the subsequent step (B), the reaction of the methylenephthalide
of formula (III) and hydrazine can usually be carried out in the presence of a
solvent at a temperature ranging from room temperature to the boiling point
of the solvent, preferably at a temperature of 80C to about 130C. Though
the hydrazine can be used in any state and in any content, it is convenient to
use an 80% aqueous solution of hydrazine hydrate. It can be used in an amount
of about 2-10 moles, preferably about 3-6 moles, per 1 mole of the methylene-
phthalide of formula (III). The solvent is not particularly limited. Those
miscible with water are preferable. Examples of the preferable solvent include
- 10 -
~.~L5164~
alcohols such as methanol, cthanol, propanol and butanol; ethcrs such as
tetrahydrofuran and dioxane; dimethyl sulfoxide; dimethylformamide; and the
mixtures of these solvents with water.
When, for example, an 80% aqueous solution of hydrazine hydrate is
used as a source of hydrazine and n-propanol as a solvent, the isolation of the
compound of formula (IV) from the reaction mixture can easily be carried out
by cooling the reaction mixture after the reaction and then collecting the
resulting crystalline precipitates by filtration. When an ~0% aqueous solution
of hydrazine hydrate is reacted while using ethanol as a solvent, the isolation
can easily be performed by concentrating the liquid reaction mixture under
reduced pressure after the reaction and recrystallizing the residue from ethanol.
Next, the subsequent step (C) will be described.
In the hydrolysis of step (C) for obtaining 4-substituted methyl-l-
phthalazone of formula (V) from the compound of formula (IV), either acid or
base may be used as the hydrolyzing reagent. As an acid, mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid are prefer-
able although organic sulfonic acids such as benzenesulfonic acid, p-tolucne-
sulfonic acid and methanesulfonic acid can also be used. As a base, alkali
hydroxides such as sodium hydroxide, potassium hydroxidc, alkali carbonates
such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate and
sodium hydrogen carbonate and alkaline earth metal hydroxides such as calcium
hydroxides are used pre:Eerably.
The hydrolyzing agent is used in an amount of 1-20 equivalents and
usually 2-5 equivalents to the compound of formula (IV).
The solvent for the reaction is not particularly limited. Water and
solvents miscible with water are preferable, of which examples include alcohols
such as methanol, ethanol and propanol; ketones such as acetone and methyl-
- 11 -
~51~i4~3
ethylketone; ethers such as cyclic ethers, for example, tetrahydrofuran and
dioxane; and mixtures of water and these water-soluble solvents.
The reaction can be carried out at a temperature ranging from room
temperature to the boiling point of the solvent, preferably about ~0C to 110C.When the hydrolysis is carried out with hydrochloric acid and using
water as a solvent, the isolation of 4-substituted methyl-l-phthalazone of
formula (V) from the reaction mixture can be achieved by collecting the
deposited crystals after the reaction by filtration to obtain a crude product
and, if necessary, recrystallizing it from, for example, a solvent mixture of
uater and acetone.
The next step (D), i.e. the halogenation of the 4-substituted
methyl-l-phthalazone of formula (V), is usually carried out in a solvent with
a halogenating agent. Said halogenating agent is not particularly limited.
Preferred halogenating agents are, for example, chlorine, bromine,
N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, sulfuryl chloride,
cupric chloride, cupric bromide, phosphorus trichloride, phosphorus tribromide
and phosphorus pentachloride. The halogenating agent is used in an amount of
0.5-2.0 moles, preferably 1.0-1.3 moles, per l mole of the 4-substituted
methyl-l-phthalazone of formula (~).
The solvent used in thc reaction is not particularly limited so long
as it is inert to the reaction. It may also be selected in accordance with the
kind of the halogenating agent used. Generally, halogenated hydrocarbons such
as methylene chloride, chloroform and carbon tetrachloride; ethers such as
ethyl ether, tetrahydrofuran, dioxane; organic acids such as formic acid, aceticacid and propionic acid; dimethylformamide; and water are used.
The reaction can be preferably carried out at a temperature ranging
l:~Sl1~8
from room temperature (about 20C) to th0 boiling point of the solvent and is
usually completed within 1~ hours.
~hen bromine is used as the halogenating agen~, acetic acid as the
solvent and R4 in formula (VI) is -COOII, the isolation of 4-~-halogeno-~-
substituted methyl)-l-phthalazone of formula ~VI) from the reaction mixture can
be performed by distilling off the solvent after the reaction, adding water to
the residue, collecting the resulting crystals by filtration and, if necessary,
recrystallizing them with a mixture of acetone and hexane.
~hen R4 in formula (VI) is -CONH2, bromine is used as the halogenating
agent and acetic acid as the solvent, the isolation can be carried out by
distilling off the solvent after the reaction, dissolving the residue into
chloroform, washing the chloroform solution with cold water, drying it over
anhydrous sodium sulfate, filtering off the drying agent, concentrating the
filtrate under reduced pressure and recrystallizing the residue from chloroform.The next step ~E) for converting the 4-(~-halogeno-~-substituted
methyl)-l-phthalazone of formula (VI) to the 4-hydroxymethyl-1-phthalazone of
formula ~VIII) is described below.
Firstly, (a~ of step (E), i.e. the direct hydrolysis and decarboxyla-
tion of the compound of formula (VI), will be described.
The hydrolysis of the compound of formula (VI) can be carried out in
the same manner as in the compound of formula (IV) of step (C). When an acid is
used in this hydrolysis as a hydrolyzing agent, the hydrolysis and the
decarboxylation can be effected simultaneously. According to the present
invention, when the hydrolysis is carried out with a base, there is usually
formed in the course of the reaction a salt of 7-alkoxycarbonyl-6, 8-dimethyl-
l-phthalazone-4-~-hydroxyacetic acid represented by the following formula:
C~l (0~1) COO~I
RlOOC ~h (IX)
CH3 O
wherein Rl is as defined above. In thi~ case, the compound of this invention,
formula ~IX), may be decarboxylated either after the isolation of said compound
or without isolation. The decarboxylation of the compound of formula ~IX) can
be effected in either neutral or acidic conditions. It is generally preferable
to carry out the decarboxylation under an acidic condition. Various acids can
be used for the acidic condition. For example, formic acid, acetic acid,
propionic acid, benzenesulfonic acid, toluenesulfonic acid, phenylacetic acid
are preferable organic acids and sulfuric acid, hydrochloric acid and nitric
acid are preferable inorganic acids.
The solvent may or may not be used. When a solvent is used, it is
not particularly limited so long as it is inert to the reaction. Water alone
is also usable. Preferred solvents include aromatic hydrocarbons such as
benzene, toluene and xylene; alcohols such as methanol, ethanol and propanol;
organic acids such as formic acid, acetic acid and propionic acid; ketones such
as acetone and methyl ethyl ketone; ethers such as cyclic ether, for example,
dioxane and tetrahydrofuran; and their mixtures with water.
In the hydrolysis of the compound of formula (VI), the acid is used
as a catalyst, so that its amount is not particularly limited and usually its
0.01-1.0 equivalent is employed. The reaction temperature and reaction time
are selected from wide ranges in accordance with the kind of acid or base and
- 14 -
~5~64a
the solvent used. Nhen a solvent is used, the reaction is preferably carried
out at a temperature ranging from room te~perature to the boiling point of the
solvent. The reaction is usually completed in 1-10 hours.
When a solvent mixture comprising water and an organic solvent is
used in the reaction, the isolation of the 4-hydroxymethyl-1-phthalazone of
formula (VIII) from the reaction mixture is carried out by distilling off the
organic solvent, adding water to the residual reaction mixture, adjusting its
pH to about 4 with a base or an acid and collecting the deposited crystals by
filtration.
Next, ~b) of step (E) will be described.
When R4 of the compound of formula (VI) is -COOH, the hydrolysis and
the decarboxylation can be carried out more preferably by method (b), although
it can also be carried out by method (a).
According to the first method of (b), decarboxylation also takes
place simultaneously when the carboxylic acid salt of formula (VII) is reacted
with 4-(~-halogeno-~-substituted methyl)-l-phthalazone of formula (VI), so that
a subsequent hydrolysis can give the objective compound.
The following intermediate is formed by the reaction of the carboxylic
acid salt of formula (VII) with the compound of formula (VI) and simultaneous
decarboxylation:
o
C1120C-R5
~13 ~ ~ (X)
C~13 0
_ 15 -
~15~6~8
wherein Rl and R5 are as defined al~ove. Either the resultant reaction mixture
or the intermediate isolated from said mixture can be used in the subsequent
hydrolysis process.
The reaction between the compound of formula (VI) and the carboxylic
acid salt of formula (VII) is usually carried out in the presence of a solvent.
Solvents inert to this reaction can be used for this purpose, of which examples
include fatty acids such as formic acid, acetic acid and propionic acid;
ketones such as acetone and methyl ethyl ketone; ethers such as cyclic ethers,
for example, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene,
lQ toluene and xylene; dimethyl sulfoxide and dimethylformamide.
If, in this reaction, a fatty acid salt is used as the carboxylic
acid salt of formula ~VII) and a fatty acid is used as the solvent, it is prefer-
able to use, as the solvent, the fatty acid corresponding to said carboxylic
acid salt of formula (VII). For example, when the carboxylic acid salt of
formula ~VII) is sodium acetate, the solvent is preferably acetic acid.
The carboxylic acid salt of formula (VII~ is used usually in an
amount of 1-10 moles, preferably 1.5-5 moles, per 1 mole of the compound of
formula (VI).
The reaction temperature and the reaction time are selected from
~ide ranges in accordance with the kinds of starting material and solvent. It
is usually preferable to carry out the reaction at a temperature between room
temperature (about 20C~ to the boiling point of the solvent used in the
reaction. The reaction is usually completed in about 10 hours.
Examples of R5 in the formula (VII) are a hydrogen atom, an alkyl
such as methyl, ethyl, propyl, butyl, pentyl, hexyl and heptadecyl, an aryl
such as phenyl and naphthalyl and an aralkyl such as benzyl, phenylethyl and
- 16 -
11 S~6~L~
naphthylmethyl. The alkyl may be in a straight chain or branched if possible.
Further, these alkyl, phenyl, or naphthyl may be substituted with other
substituents other than hydrogen unless they have an undesirable effect on the
reaction.
The examples of M in the formula (VII) are alkali metals such as
sodium and potassium and alkaline earth metals such as calcium and magnesium,
pr~vided that n is 1 when M is an alkali metal and n is 2 when M is an alkaline
earth metal. It is sometimes preferable to carry out this reaction in the
presence of a catalyst. Particularly when the above-mentioned ketones, cyclic
ethers or aromatic hydrocarbons are used as the solvent, the reaction is
preferably conducted in the presence of a catalyst such as a crown ether
typified by 18-crown-6, among which 18-crown-6 itself is particularly prefer-
able. It can be added in an amount of about 0.1-10% (by weight), preferably
about 1-5% based on the carboxylic acid salt of formula (VII).
The subsequent step of hydrolysis can be carried out in the same
~ay as the hydrolysis in the first step of (C).
Next, the second method of (b), wherein decarboxylation is carried
out at the beginning and followed by the reaction with the carboxylic acid salt
of formula ~VII) and hydrolysis, will be described.
The first decarboxylation from the compound of formula (VI) can be
carried out by a mere heating in the presence or absence of a solvent. It is
preferably carried out in a solvent inert to the reaction. Examples of the
solvent are organic acids such as formic acid, acetic acid and propionic acid
and aromatic hydrocarbons such as benzene, toluene, and xylene.
The reaction can be carried out at the temperature from 50C to
250C in general. The reaction is most preferably carried out at the temperature
~5~64~
from 80C to 1?0C in the presence of the solvent. The reaction time varies
depending on the temperature. The reaction usually can be completed in the
range of from several minutes to about 3 hours.
By the decarboxylation~ there is formed a compound represented by
the following formula:
CH2X
CH3 ~ (XI)
R OOC /
1 CH3 0
wherein Rl and X are as defined above, as an intermediate. This intermediate
may be isolated before reacting it with the carboxylic acid salt of formula
(VII) in the subsequent step but the reaction mixture including said inter-
mediate can also be used in the subsequent step. The reaction of saidintermediate and the carboxylic acid salt of formula ~VII) can be effected in
the same way as in the above-mentioned reaction between the compound of formula
~VI) and the carboxylic acid salt of formula ~VII).
By the reaction between the compound of formula ~XI) and the
carboxylic acid salt of formula ~VII), the above-mentioned compound of
formula ~X) is formed as an intermediate. Ilydrolysis of this compound of
formula ~X) can be effected in the same manner as above.
Lastly, ~c~ of step ~) will be described. ~hen R~ in formula ~VI)
is -CONH21 the reaction of the compound of formula (VI) and the carboxylic acid
salt af formula (VII) can be performed in the same way as the reaction in the
method ~b) of step ~E).
- 18 -
~S1~8
Simultaneous hydrolysis and decarboxylation of the acyloxylated
compound can be carried out in the same way as the hydrolysis using an acid in
step ~C).
Tlle objective compound thus obtained, i.e. 4-hydroxymethyl-1-
phthalazone of formula ~VIII) J can be isolated by removing the organic solvent
by a method such as distillation, followed by adjusting the pH to about 4 and
collecting the deposited crystals by filtration, when a solvent mixture
comprising water and an organic solvent is used as the solvent.
This process will be further described by the following examples~
which are presented in no limitative way.
Example 1
Benzene ~10 ml) is added to a mixture of 2.50 g of 3,5-dimethyl-4-
ethoxycarbonylphthalic anhydride and 4.35 g of methoxycarbonylmethylenetri-
phenylphosphorane, and the mixture is reacted at room temperature with stirring
for 4 hours. After the reaction, the solvent is distilled off under reduced
pressure to give a crude product. It is subjected to a column chromatography
using 150 g of silica gel and a benzene-ethyl acetate mixture as the developing
solvent, whereby the two products having a relation of geometric isomer to
each other can be isolated:
methyl (Z)-5~7-dimethyl-6-ethoxycarbonyl-phthalide-~3~-methylene
carboxylate; 2.20 g (yield 72.3%); m.p. 122.0-122.5C
methyl (E)-5,7-dimethyl-6-ethoxycarbonyl-phtllalide-~3'C~-methylene-
carboxylate; 0.34 g (yield 11.2%); m.pO 134-136C.
Example 2
Benzene (30 ml) is added to a mixture of 3.72 g of 3,5-dimethyl-4-
ethoxycarbonylphthalic
- 19 -
~15~8
anhydride and 6. 20 g of ethoxycarbonyl~ethylenetriphenylphosphorane and the mix-
ture is reacted at room temperature for 3 hours with stirring. After the reac-
tion the deposited crystals are collect~ed by filtration, and there is obtained
1.23 g (yield 25.8%) o ethyl (Z)-5,7-dimethyl-6-ethoxycarbonylphthalide-~3' -
methylenecæboxylate; m.p. 114-114.5C.
The filtrate is concentrated, and the residue is subjected to silica
gel chrcmatography in the sa~e manner as in Example 1, and there is additionally
obtained 2.11 g (yield 44.2%) of ethyl (Z)-5,7-dimethyl-6-ethoxyc æbonyl-
phthalide-~3'a-methylenec æboxylate. sy this chromatography, there is simultane-
ously obtained 0.80 g (yield 16.8%) of ethyl OE)-5,7-dimethyl-6-e~hoxyc æbonyl-
phthalide-~3'a-methylenecarboxylate; m.p. 105-108 C.
Example 3
Benzene (3 ml) is added to a mixture of 0.50 g of 3,5-dimethyl-4-
methoxy bonylphthalic anhydride and 0.97 g of ethoxycarbonylmethylenetriphenyl-
phosphorane, the mixture is reacted at room temFerature for 3 hours with stirr-
ing and the deposited crystals æe collected by filtration, whereby 0.26 g
(yield 40.1%) of ethyl (Z)-5,7-dimethyl-6-methoxycarbonylphthalide-~3'a-
methylene boxylate is obtained; m.p. 127-128.5 C.
Example 4
Ethyl (Z)-5,7-dimethyl-6-ethoxycarbonylphthalide-~3'a-methylene-
carboxylate (2.48 g) is added into a mixture of 50 ml of n-propanol and 4.70 g
of 80~ aqueous solution of hydrazine hydrate, and then the mixture is heated
under reflux at llo& for 10 hours. The reaction mixture is cooled and the de-
posited crystals are collected by filtration to obtain 2.25 g (yield 90.7%) of
6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-acetic acid hydrazide.
m.p. 243-245C (decomposition with foaming).
IR spectrum: vKmBx (cm ) = 3320, 3180, 1724, 1655, 1604, 1526, 1280
- 20 -
.~
l~S~
NMR spectrum (DMSO-d6): ~ = 1.35 (t, 3H, J = 7Hz; COE12C_3), 2.39, 2.78
(s, s, 3H, 3H; phenyl-CH3), 3.72 (s, 2H; CH2), 4.40 (q, 2H, J = 7Hz;
OC_2CH3), 3.5-4.7 (broad, 2H, NH2), 7.60 (s, lH; phenyl-H), 9.25
(s, LH; NHNH2), 12.36 (s, lH; NH-N =)
Example 5
Ethyl (E,Z)-5,7-dimethyl-6-ethoxycarbonylphthalide-~3'~-methylene-
carboxylate [the a~ove-mentioned geometric isamer mixture, (III') : (III") = 9 :
41 (0.33 g) is dissolved into 7 ml of n-propanol, to which is added 0.63 g of
80% aqueous solution of hydrazine hydrate. me reaction and the after-treatment
are ~rried out in the same manner as in Example 4, whereby 0.31 g (yield 93.6%)
of 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-acetic acid hydrazide is ob-
tained.
mis product perfectly coincides with the product of Example 4 in m.p.,
IR and NMR spectra.
Example 6
Ethyl (Z)-5,7-dimethyl-6-methoxycarbonylphthalide-~3'~-methylene-
carboxylate (0.20 g) is dissolved into 4 ml of n-propanol, to which is addbd
0.41 g of 80% aqueous solution of hydrazine hydrate. m ereafter, the reaction
and the after-treatment are carried out in the same manner as in Example 4.
Thus 0.14 g (yield 68.2%) of 6,8-dimethyl-7-methoxycarbonyl-1-phthalazone-4-
aoe tic acid hydrazide is obtained.
m.p. 257.5-259.0C (decomposition with foaming).
IR spectr~m: vKmBrx (cm 1) = 3300, 3170, 3040, 2940, 1725, 1650, 1603, 1532,
1435, 1285
NMR spectrum (LMSO-d6): ~ = 2.38, 2.76 (s, s, 3H, 3H; phenyl-CH3), 3.72
(s, 2H; CH2), 3.94 (s, 3H; CH30), 3.6-4.7 (broad, 2H; NH2), 7.64
(s, lH; phenyl-H), 9.26 (s, lH; NHNH2), 12.38 (s, lH; NH-N =)
Example 7
3,5-Dimethyl~4-ethoxycarbonylphthalic anhydride (25.0 g) and 43.5 g of
methoxycarbonylmethylenetriphenylphosphorane are added to 100 ml of benzene and
stirred at 20-25C for 4 hours. After the reaction, the reaction mLxture is con-centrated under reduced pressure, the residue is added into 800 ml of n-propanoland 64.0 g of 80% aqueous solution of hydrazine hydrate is added, and the mix-
ture is heated under reflux for 10 hours. m e reaction mixture is cooled and
the depositing crystals are collected by filtration. mus, 27.2 g (yield 85.4%)
of 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-acetic acid hydrazide is ob-
tained. This product perfectly coincides with the product of Example 4 in m.p.,
IR and NMR spectra.
Example 8
6,8-Dimethyl-7-ethoxy OE bonyl-l-phthalazone-4-acetic acid hydrazide
(12.00 g) is added to 380 ml of 2 N hydrochloric acid and heated under reflux
for 5 hours. The reaction mixture is cooled and the depositing crystals are
collected by filtration, washed with water and dried. Thus, 10.2 g (yield 89.0%)of 6,8-dimethyl-7-ethoxy OE bonyl-l-phthalazone-4-acetic acid is obtained.
m.p. 162.5-163.5C (decomposition with foaming).
IR spectrum: ~m~3rx (cm 1) = 3240, 2300-3000 (broad), 1730, 1700 (shoulder),
1640, 1602, 1280
NMR spectrum (DMSO-d6): ~ = 1.37 (t, 3H, J = 7Hz; OCH2C_3), 2.42, 2.82
(s, s, 3H, 3H; phenyl-CH3), 3.94 (s, 2H; CH2), 4.43 (q, 2H, J = 7Hz;
OC_2CH3), 2-6 (broad, lH; COOH), 7.61 (s, lH; phenyl-H), 12.45
(s, lH; NH)
Example 9
6,8-Dimethyl-7-methoxycarbonyl-1-phthalazone-4-acetic acid hydrazide
(2.00 g) is added to 50 ml of 3 N hydrochloric acid and heated under reflux or
5i~
2 hours, after which it is treated in ~le same msnner as in Example 8. Thus,
1~80 g (yield 94.4%) of 6,8-dimethyl-7-methoxycarbonyl-1-phthalazone-4-acetic
acid is obtained.
m.p. 203-205C (decomposition with ~oamlng).
IR spectrum: vmar (cm 1) = 3300, 3160, 3035, 2300-3000 (broad), 1733, 1697,
1663, 1603, 1438, 1290, 1250, 1175, 1145
NMR spectrum (~MSO-d6~: ~ = 2.40, 2.78 (s, s, 3H, 3H; phenyl-CH3), 3.96
(s, 5H; CH2, CH30), 5-10 (broad, lH; COOH), 7.61 (s, lH; phenyl-H),
2.45 (s, lH; NH)
Example 10
6,8-Dimethyl-7-ethoxyc æbonyl-1-phthalazone-4-aoetic acid (0.40 g) is
dissolved into 10 ml of glacial acetic acid, 0.24 g of brcmine is added thereto,
an~ the mixture is reacted at room temperature for 3 hours with stirring. m e
acetic acid is distilled off under reduoe d pressure, water is added to the
residue, the deposited crystals æe collected by filtration and the crystals
recrystallized from acetone-n-hexane mixture. Thus, 0.47 g (yield 92.9%) of
6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoacetic acid is obtained.
m.p. 202.5-204C.
IR spectrum: ~KmBx (cm ) = 3170, 2200-3000 (broad), 1730, 1660, 1605, 1278,
1240, 1145, 1120
NMR spectrum (DMSC-d6): ~ = 1.40 (t, 3H, J = 7Hz; OCH2CH3), 2.45, 2.80
(s, s, 3H, 3H; phenyl-OEl3), 4.46 (q, 2H, J = 7Hz; OC_2CH3), 4-7 (broad,
lH; COOH), 6.47 (s, lH; CHBr), 7.87 (s, lH; phenyl-H), 12.77 (s, lH; NH)
Example 11
6,8-Dimethyl-7-ethoxyc æbonyl-1-phthalazone-4-acetic acid (1.00 g) is
dissolved into 20 ml of glacial acetic acid, 0.61 g of sulfuryl chloride is
added thereto, and the mixture is reacted at room temperature for 7 hours with
- 23 -
`~,r
115~648
stirring. The mixture is concentrated under reduced pressure and the residue is
recrystallized from an acetone-n-hexane mixture. m us, 1.00 g (yield 89.4%) of
6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-chloroacetic acid is obtained.
m.p. 188-189& -
IR spectrum: vm3X (cm ) = 3026, 2200-3000 (broad), 1730, 1663, 1603, 1277,
1240, 1150, 1120
NMR spectrum (DMSO-d6): ~ = 1.38 (t, 3H, J = 7Hz; OCH2C_3), 2.46, 2.82
(s, s, 3H, 3H; phenyl-CH3), 4.45 (q, 2H, J = 7Hz; OCH2CH3), 4-7 (broad,
COOH), 6.40 (s, lH; ClCH), 7.85 (s, lH; phenyl-H), 12.77 (s, lH; N~)
Example 12
6,8-Dimethyl-7-methoxycarbonyl-1-phthalazone-4-acetic acid (1.27 g) is
suspended in 40 ml of glacial acetic acid, 0.77 g of sulfuryl chloride is added
thereto, the mixture is reacted at rcom temperature for 4 hours with stirring,
and thereafter it is treated in the same manner as in Example 11. Thus, 1.10 g
(yield 77.4%) of 6,8-dimethyl-7-methoxycarbonyl-1-phthalazone-4-~-chloroaoe tic
acid is obtained.
m p. 249-250& (decomposition).
IR spectrum: ~KmBx (cm 1) = 3160, 3040, 2930, 2300-3000 (broad), 1730, 1667,
1603, 1440, 1283, 1242, 1145, 1118
NMR spec~mm (~MSO-d6): ~ = 2.42, 2.78 (s, s, 3H, 3H; phenyl-CH3), 3.96
(s, 3H; CH30), 6.38 (s, lH; CHCl), 7.83 (s, lH; phenyl-H), 9.32 (broad,
lH; COOH), 12.75 (s, lH; NH)
Example 13
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoaoe tic acid
(3.80 g) is dissolved into 100 ml of glacial aoe tic acid and heated at 100C for
2 hours with stirring. m e reaction mixture is concentrated under reduoe d pres-sure, water is added to the residue, and ~he resulted crystals are collected by
- 24 -
~5~6~8
filtration to obtain a crude product. It is recrystallized from benzene, and
there is obtained 2.90 g (yield 85.5%) of ethyl 4-bromomethyl-6,8-dimeth~
phthalazone-7- OE boxylate.
m.p. 202-203& .
Example 14
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-chloroacetic acid
(3.40 g) is dissolved into 100 ml of glacial acetic acid and the mixture is
reacted and after-treated in the same manner as in Example 13. mus, 2.65 g
(yield 89.9~) of ethyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
is obtained.
m.p. 184-186 & .
Example 15
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-chloroacetic acid
(0.50 g) is dissolved into 20 ml of toluene and reacted at 90 & for 2 hours withstirring. The mixture is cooled and the deposited crystals are collected by
filtration. mus, 0.31 g (yield 70.1%) of ethyl 4-chloromethyl-6,8-dimethyl-1-
phthalazone-7-carboxylate is obtained. It coincides with the product of Example
14 in melting point.
Example 16
6,8-Dimethyl-7-methoxycarbonyl-1-phthalazone-4-~-chloroacetic acid
(0.97 g) is dissolved into 30 ml of glacial acetic acid and reacted and after-
treated in the same manner as in Example 13. Thus, 0.73 g (yield 86.7%) of
methyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 253-255C.
Example 17
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-acetic acid (2.00 g) is
dissolved into 50 ml of glacial acetic acid, to which is added 1.20 g of brcmine.
- 25 -
~S~6~8
The mixture is reacted at room temperature for 3 hours and then heated at 100 C
for 2 hours. The reaction mixture is cooled, water is added thereto, the de-
posited crystals are collected by filtration, and the crystals are recrystallized
from benzene. Thus, 1.80 g (yield 80.4%) of e~yl 4-brom~methyl-6,8-dimethyl-1-
phthalazone-7-carboxylate is obtained. This product perfectly coincides with
the product of Example 13 in melting point.
Example 18
Ethyl 4-bromomethyl-6,8-limethyl-1-phthalazone-7-carboxylate (3.40 g)
is dissolved into 50 ml of d~nethylformamide, 2.04 g of sodium formate is then
added thereto, and the mixture is reacted at 60 & for 1 hour with stirring. The
reaction mixture is concentrated under reduced pressure to distil off the sol-
vent, water is added to the residue, the resultant crystals are collected by
filtration, and the crystals are recrystallized from ethanol. Thus, 2.42 g
(yield 79.6%) of ethyl 6,8 dimethyl-4-formyloxymethyl-1-phthalazone-7-carboxy-
late is obtained.
m p 152-154& .
Example 19
Ethyl 4-bromcmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (15.00 g)
is dissolved into 300 ml of glacial acetic acid, then 10.80 g of sodium aoe tate
is added thereto, and the mixture is reacted under reflux with stirring and heat-
ing for 7 hours. The reaction mixture is treated in the same manner as in
Example 18, and there is obtained 13.65 g (yield 97.0%) of ethyl 4-acetoxymethyl-
6,8-dimethyl-1-phthalazone-7-carboxylate.
m.p. 162-164&.
Example 20
Ethyl 4-brcmomethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (3.40 g) is
dissolved into 40 ml of dimethylform~mide, 2.89 g of sodium propionate is added
- 26 -
.~
~5~l~;48
thereto, ~ld the mixt.ure is reacted at 60 C for 1 hour. The reaction mixture is
conoentrated under reduced pressure. The residue is dissolved into 200 ml of
ethyl acetate, the solution washed with water and dehydrated and dried over
magnesium sulfate. The magnesium sulfate is filtered off, the filtrate is con-
centrated under reduoed pressure, and the residue is recrystallized frcm ethanol.
mus, 2.79 g (yield 84.7%) of ethyl 6,8-dimethyl-4-propionyloxymethyl-1-phthala-
zone-7-carboxylate is obtained.
m.p. 130-132&.
B ample 21
Ethyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (2.95 g)
is dissolved into 110 ml of dimethylformamide, 9.20 g of sodium stearate is
added thereto, and the mLxture is reacted at 60& for 2 hours. me reaction mix-
ture is concentrated under reduced pressure. The residue is dissolved into
500 ml of ethyl acetate, the solution thoroughly washed wi~h warm water and then
concentrated under reduced pressure to obtain a crude product. It is subjected
to silica gel column chromatography by the use of a benzene-ethyl acetate sol-
vent mixture, and there is obtained 3.61 g (yield 66.3%) of ethyl 6,8-dimethyl-
4-steæ oyloxymethyl-1-phthalazone-7-cæboxylate.
m.p. 91-93C.
Example 22
Ethyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (2.95 g)
is dissolved into 60 ml of tetrahydrofuran, then 2.88 g of sodium benzoate and
0.2 g of 18-crown-6 are added thereto, and the mixture is reacted at 50C for 2
hours. The reaction mixture is concentrated under reduced pressure to distil
off the solvent, water is added to the residue, the precipitated crude crystals
are collected by filtratio~, and then it is recrystallized frcm ethanol. m us,
2.90 g (yield 76.2%) of ethyl 4-benzoyloxymethyl-6,8-dimethyl-1-phthalazone-7-
~151~48
carboxylate is obtained.
m.p. 178-179&.
Example 23
Ethyl 4-chloromethyl-6,8-di~ethyl-1-phthalazone-7-carboxylate (2.95 g)
is dissolved into 60 ml of tetrahydrofuran, then 4.06 g of sodium p-nitrophenyl-
acetate and 0.20 g of 18-crown-6 are added thereto, and thereafter the reaction
and the after-treatment of the mixture are carried out in the same manner as in
Example 22. The crude crystals are collected by filtration and recrystallized
from a solvent mixture comprising ethanol and chloroform. Thus, 3.70 g (yield
84.3%) of ethyl 6,8-dLmethyl-4-p-nitrophenylacetoxymethyl-1-phthalazone-7-
carboxylate is obtained.
m.p. 222.5-223& (decomposition with foaming).
Example 24
Methyl 4-chlo mmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (0.11 g)
is dissolved into 3 ml of glacial aoetic acid, then 0.32 g of sodium acetate is
added thereto, and the mixture is reacted under reflux for 40 hours with stirr-
ing. The reaction mixture is treated in the same manner as in Example 18 to ob-
tain a crude product. It is recrystallized from methanol, and there is ohtained
0.10 g (yield 84.3%) of methyl 4-acetoxymethyl-6,8-dimethyl-1-phthalazone-7-
carboxylate.
m.p. 185-187&.
Example 25
n-Propyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(0.31 g) is dissolved into 6.2 ml of glacial acetic acid, to which is added
0.49 g of sodium acetate. me mixture is reacted under reflux for 20 hours with
stirring. The reaction mixture is treated in the same manner as in Example 18
and there is obtained 0.31 g (yield 93.9%) of n-propyl 4-acetoxymethyl-6,8-
- 28 -
1:~5~648
dimethyl-l-phthalazone-7-carboxylate.
m.p. 141-142& .
Example 26
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoacetic acid
(3.83 g) is dissolved into 50 ml of formic acid, to wh ch is added 3.40 g of
sodium formate. With stirring, the mixture is reacted at 105 & for 17 hours.
After the reaction, the formic acid is distilled off under reduoe d pressure,
water is added to the residue and the deposited crystals are collected by filtra-
tion. mus, 2.85 g (yield 93.7%) of ethyl 6,8-dimethyl-4-formyloxymethyl-1-
phthalazone-7-cæboxylate is obtained.
This product perfectly coincides with the product of Example 18 in
melting point.
Example 27
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoaoe tic acid
(3.83 g) is dissolved into 70 ml of glacial acetic acid, to which is added
3.28 g of sodium aoetate. m e mixture is heated at 120& with stirring and
reacted for 6 hours. After the reaction, the aoetic acid is distilled off under
reduoed pressure, water is added to the residue, and the deposited crystals are
collected by filtration. Thus, 3.14 g (yield 98.6%) of ethyl 4-a oetoxymethyl-
6,8-dimethyl-1-phthalazone-7-carboxylate is obtained.
m is product perfectly coincides with the product of Example 19 in
melting point.
Example 28
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-chloroaoe tic acid
(3.39 g) is dissolved into 70 ml of glacial aoe tic acid, to which is added
3.28 g of sodium aoetate. m ereafter, the reaction and the after-treatment are
carried out in the same m~nner as in Example 27. m us, 3.10 g (yield 97.4%) of
- 29 -
1151648
ethyl 4-acetoxymethyl-6,8-dimethyl-1-phthalazone-7-carboxylate is obtained.
This product perfectly coincides with the product of Example 19 in melting point.
Example 29
6,8-Dimethyl-7-methoxycarbonyl-1-phthalazone-4-~-chloroacetic acid
(0.97 g) is dissolved into 20 ml of glacial acetic acid, to which is added
1.30 g of sodium acetate. Thereafter, the reaction and the after-treatment are
carried out in the same manner as in Example 27. Thus, a crude product obtained
is recrystallized from methanol to give 0.67 g (yield 73.4%) of methyl 4-acetoxy-
methyl-6,8-dimethyl-1-phthalazone-7-carboxylate.
m.p. 185-187C.
Example 30
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-acetic acid (0.91 g) is
dissolved into 20 ml of glacial acetic acid, to which is added 0.57 g of bromine.
The mixture is reacted at room temperature for 3 hours with stirring, after
which 0.99 g of sodium acetate is added and the resulted mixture is heated under
reflux for 6 hours. m e reaction mixture is concentrated under reduoe d pressure
to distil off the solvent and the deposited crystals are collected by filtration.
Thus, 0.94 g (yield 98.5%) of ethyl 4-aoe toxymethyl-6,8-dimethyl-1-phthalazone-7-
boxylate is obtained. This product perfectly coincides with the product of
Example 19 in melting point.
Example 31
Ethyl 4-aoetoxymethyl-6,8-dimethyl-1-phthalazone-7- boxylate (6.40 g)
is dissolved into a mixture of 60 ml of 1 N sodium hydroxide solution and 60 ml
of methanol and hydrolyzed at 20 & for 3 hours with stirring. After the reac-
tion the methanol is distilled off, and pH of this concentrated mixture is ad-
justed to 4 with 10% hydrochloric acid. m e deposited crystals are collected by
filtration and this crude crystals are recrystallized from aqueous ethanol.
- 30 -
~51648
Thus 4.40 g (yield 79.6%) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-
carboxylate is obtained.
m.p. 171.5-173C.
This pro uct perfectly coincides with otherwise synthesized authentic
sample in IR, IIMR and W spectra.
ExaMple 32
Ethyl 4-acetoxymethyl-6,8~dimethyl~1-phthalazone-7-carboxylate (3.18 g)
is dissolved into a mixture comprising 30 ml of 1 N hydrochloric acid and 30 ml
of methanol and hydrolyzed at 60C for 5 hours with stirring. After the reac-
tion, the methanol is distilled off, pH of the concentrated mixture is adjustedto 4 with 10% sodium hydroxide solution, and thereafter treated in the same
manner as in Example 31. Thus, 2.10 g (yield 76.0%) of ethyl 6,8-dimethyl-4-
hydroxymethyl-l-phthalazor,e-7-carboxylate is obtained.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 33
Ethyl 6,8-dimethyl-4-formyloxymethyl-1-phthalazone-7-carboxylate
(3.04 g) is dissolved into a mixture comprising 30 ml of 1 N sodium hydroxide
solution and 30 ml of methanol and hydrolyzed at 20C for one hour with stirring,
after which it is treated in the same manner as in Example 31. Thus, 2.25 g
(yield 81.4%) of ethyl 6,8-dimethyl-4~hydroxymethyl-1-phthalazone-7-carboxylate
i5 obtained.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and UV spectra.
- 31 -
~S1648
Example 34
Ethyl 6,8-dim~thyl-4-propionyloxymethyl-1-phthalazone-7-carboxylate
(3.~8 g) is dissolved into a mixture comprising 30 ml of 1 N sodium hydroxide
solution and 30 ml of methanol and hydrolyzed at 20& for one hour with stirring
and then the xeaction nNxture is treated in the same manner as in Example 31.
m us, 2.14 g (yield 77.8%) of ethyl 6,8-dimethyl-4-hydLox~methyl-l~phthalazone-
7-carboxylate is obtained.
m.p. 171-173C.
This product perfec~ly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 35
Ethyl 6,8-dimethyl-4-stearoyloxymethyl-l~phthalazone-7-carboxylate
(2.17 g) is dissolved into a mixture comprising 30 ml of 1 N sodium hydroxide
solution and 30 ml of methanol and hydrolyzed at 20 & for 2 hours with stirring
and then the reaction mixture is treated in the same manner as in Example 31.
Thus, 0.81 g (yield 73.4%) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-
7-carboxylate is obtained.
m.p. 171-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in NMR, IR and W spectra.
Example 36
Ethyl 4-benzoyloxymethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(1.90 g) is dissolved into a mixture comprising 20 ml of 1 N sodium hydroxide
solution and 20 ml of methanol and hydrolyzed at 20C for 5 hours with stirring
and then the reaction mixture is treated in the same manner as in Example 31.
Thus, 0.94 g (yield 68.0%) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-
7-carboxylate is obtained.
m.p. 171.5-173& .
- 32 -
~16~
This prcduct perfectly coincides with ot~rwise synthesized authentic
sample in IR, NMR and W spectra.
Example 37
Ethyl 6,8-dimethyl-4-p-nitrophenylacetox~methyl-1-phthalazone-7-
carboxylate (2.20 g) is dissolved into a mixture comprising 20 ml of 1 N sodium
hydroxide solution and 20 ml of methanol and thereafter hydrolyzed and after-
treated in the same manner as in Example 36. Thus, 0.86 g (yield 62.3%) of
ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 171.5-173&.
This product perfectly coincides with otherwise synthesized authetic
sample in IR, NMR and W spectra.
Example 38
Methyl 4-acetoxymethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(0.31 g) is dissolved into a mixture comprising 10 ml of 1 N sodium hydr~xide
solution and 10 ml of methanol and thereafter hydrolyzed and after-treated in
the same manner as in Example 31. Thus, 0.20 g (yield 76.2~) of methyl 6,8-
dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 202-203C.
mis product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 39
n-Propyl 4-acetoxymethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(1.66 g) is dissolved into a mixture comprising 20 ml of 1 N sodium hydroxide
solution and 20 ml of methanol and hydrolyzed at 20C for 2 hours with stirring
and then the reaction mixture is treated in the same manner as in Example 31.
m us, 1.23 g (yield 84.7%) of n-propyl 6,8-dimethyl-4-hydroxymethyl-1-phthala-
zone-7-carboxylate is obtained.
m.p. 179-180&.
- 33 -
l~S1~8
IR spectrum: ~m~x (cm ) = 3160, 2920, 1725, 1650, 1600, 1270, 1230, 1150,
1115, 1030
NMR spectrwm (DMSO-d6): ~ = 0.97 ~t, 3H, J = 7Hz; OCH2CH2CH3), 1.74 (multi,
2H; OCH2C_2CEI3)m 2.40, 2.77 (s, s, 3H, 3H; phenyl-CH3), 4.31 (t, 2H,
J = 7Hz; OC_2CH2CH3), 4.64 (d, 2E~, J = 6Hz; CH-2~)~ 5.4 (t, lH,
J = 6Hz; OH), 7.84 (s, lH; phenyl-H), 12.36 (s, lH; NH)
Example 40
Ethyl 4-bromcmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (1.70 g)
is added to a mixture comprising 50 ml of water and 10 ml of dioxane, to which
is added 1.30 g of sodium hydrogen carbonate. The mixture is heated under re-
flux for 10 hours to effect the hydrolysis. m e reaction mLxture is diluted
with 150 ml of water, its pH is adjusted to 3 with 10% hydrochloric acid, the de-
posited crystals are collected by filtration, and the crystals are recrystal-
lized from aqueous ethanol. m us, 1.02 g (yield 74.0%) of ethyl 6,8-dimethyl-4-
hydroxymethyl-l-phthalazone-7-carboxylate is obtained.
m.p. 171-173C.
m is product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and UV spectra.
Example 41
Ethyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (3.00 g)
is added to a mLxture comprising 100 ml of water and 10 ml of ethanol, to which
is added 2.50 g of sodium hydrogen carbonate. m e mixture is heated under re-
flux for 2 hours to effect the hydrolysis. After the reaction the mixture is
ooncentrated to distil off the solvent and the condensed mixture is treated in
the same manner as in Example 40. Thus, 2.20 g (yield 73.0%) of ethyl 6,8-
dimethyl-4~hydroxymethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 171-173C.
- 34 -
~5i6~
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 42
Ethyl 4-brcmomethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (1.00 g)
is added to a mixture comprising 23 ml of dimethylformamide and 23 ml of water,
to which is added 1.23 g of sodium aeetate. m e mixture is heated at 60C for
5 hours with stirring to effeet the hydrolysis. After the reaction, the solvent
is distilled off, water is added to the residue, its pH is adjusted to 4 with
hydrochloric acid, the deposited crystals are collected by filtration and this
crude product is recrystallized from aqueous ethanol. m us, 0.56 g (yield 68.8%)
of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 171-173C.
m is produet perfectly eoincides with otherwise synthesized authentie
sample in IR, NMR and W speetra.
Example 43
Mbthyl 4-chloromethyl-6,8-dimethyl-1-phthalazone-7-earboxylate (0.56 g)
is added to a mixture comprising 20 ml of water and 5 ml of ethanol, to which is
added 0.50 g of sodium hydrogen carbonate. Thereafter, the mixture is reaeted
and after-treated in the same manner as in Example 41. Thus, 0.39 g (yield 74.3%)
of methyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-c æboxylate is obtained.
m.p. 202-203&.
m is produet perfeetly eoineides with otherwise synthesized authentie
sample in IR, NMR and W speetra.
Example 44
n-Propyl 4-ehloromethyl-6,8-limethyl-1-phthalazone-7-e æboxylate
(0.31 g) is added to a mixture eomprising 10 ml of water and 2 ml of ethanol, to
whieh is added 0.30 g of sodium hydrogen earbonate. Thereafter, the mixture is
~5~
reacted and after-treated in ~le same manner as in Example 41. Thus, 0.20 g
(yield 68.9%) of n-propyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxy-
late is obtained~
m.p. 179-180C.
mis product perfectly coincides with the product of Example 39 in IR
amd NMR spectra.
Example 45
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-chloroa oe tic acid
(0.34 g) is added to a solution of 0.42 g of sodium hydrogen carbonate in 5 ml
of water. The mixture is heated at llo& for 6 hours with stirring to effect
the hydrolysis. After the reaction, pH of the reaction mixture is adjusted to 2
with 1 N hydrochloric acid, the separated oil is extracted with ethyl aoe tate,
the ethyl acetate layer is washed with water and dried over anhydrous magnesium
sulfate and the ethyl acetate is distilled off by con oentration under reduced
pressure. Thus, 0.26 g (yield 81%) of 6,8-dimethyl-7-ethoxycarb~nyl-1-phthala-
zone-4-~-hydroxyacetic acid is obtained.
nLp. 124-128C.
IR spectrum: vKBx (cm 1) = 3700-3000 (broad), 3321, 2996, 3000-2200, 1730,
1645, 1635, 1605, 1440, 1430, 1275, 1240
NMR spectrum (DMSO-d6): 3 = 1.35 (t, 3H, J = 7Hz; OCH2C_3), 2.38, 2.78
(s, s, 3H, 3H, phenyl-CH3), 4.42 (q, 2H, J = 7Hz; OCH2CH3), 5.33
(s, lH; CH), 4-8 (broad, 2H, C~I; COOH), 7.86 (s, lH; Phenyl-H), 12.25
(s, lH; NH)
In this Example, the 0.34 g of 6,8-dimethyl-7-ethoxycarbonyl-1-phthala-
zone-4-N-chloroa oetic acid is replaoe d with 0.38 g of 6,8-dimethyl-7-ethoxy-
carbonyl-l-phthalazone-4-~-bramoaoe tic acid, and there can similarly be obtained
0.20 g (yield 62%) of 6, 8-di~ethyl-7-ethoxycarbonyl-1-phthalazone-4-hydroxy-
acetic acid.
- 36 -
,~
l~S3~
Example 46
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-hydroxyacetic acid
(0.32 g) is added to 1 ml of 0.1 N hydrochloric acid, to which is added 5 ml of
water. The mixture is heated at 105-110& for 10 hours with stirring to effect
the decarboxylation. After the reaction, pH of the reaction mixture is adjusted
to 4 with 0.1 N sodium hydroxide solution, the deposited crystals are collected
by filtration to obtain a crude product and it is recrystallized from aqueous
ethanol. Thus, 0.21 g (yield 76%) of the objective product i.e. ethyl 6,8-
dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
In the same manner, methyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-
7-carboxylate can be obtained from 6,8-dimethyl-7-methoxycarbonyl-1-phthalazone-
4-~-hydroxyacetic acid.
m.p. 202-203C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 47
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoacetic acid
(0.50 g) is added to 20 ml of water and heated at loo& for 20 hours with stirr-
ing to effect the hydrolysis and the decarboxylation simultaneously. After the
reaction, the deposited crystals are collected by filtration, and there is ob-
tained 0.25 g (yield 69%) of the objective com~ound i.e. e~hyl 6,8-dimethyl-4-
hydroxymethyl-l-phthalazone-7-carboxylate.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
:1~5~648
Similarly, methyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-
carboxylate can be obtained from 6,8-dimethyl-7-methoxycarbonyl-1-phthalazone-4-
~brom~acetic acid.
m.p. 202-203C.
This product perfectly coincides with otherwise synthesized product in
IR, NMR and W spectra.
Example 48
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromDacetic acid
(0.38 g) is added to a solution of 0.42 g of sodium hydrogen carbonate in 5 ml
of water, after which the reaction and the after-treatment are carried out in
the same manner as in Example 45. Thus, 0.20 g (yield 62%) of the objective com~
pound i.e. 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-hydroxyacetic acid is
obtained.
m.p. 124-128&.
This product perfectly coincides with the product of Example 45 in IR
and NMR spectra.
Example 49
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-bromoacetic acid
(0.50 g) is added to 20 ml of water and heated at 100C for 20 hours with stirr-
ing to effect the hydrolysis and the decarboxylation simultaneously. After the
reaction, the deposited crystals are collected by filtration and there is ob-
tained 0.25 g (yield 69%) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-
carb~xylate.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Similarly, methyl 6,8-dimethyl-4-hydraxymethyl-1-phthalazone-7-carboxy-
- 38 -
~S;~6~
late can be obtained from 6,8-dimeth~1 7-methoxycarbonyl-1-phthalazone-4-~-brom~-
acetic acid.
m.p. 202-203&.
This product perfQctly coincides with otherwise synthesized product in
IR, NMR and W spectra.
Example 50
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-hydroxyacetic acid
(0.32 g) is added to a solution of 65 mg of concentrated sulfuric acid in 6 ml
of water, af~er which the reaction and the after-treatment are carried out in
the same manner as in Example 46. Thus, 0.17 g (yield 62%) of the objective com~
pound i.e. ethyl 6,8-dimethyl-4-hydroxymethyl-1-pl~thalazone-7-carboxylate is ob-
tained.
m.p. 171.5-173C.
This product perfectly coincides with otherwise synthesized authentic
sample in IR, NMR and W spectra.
Example 51
6,8-Dimethyl-7-ethoxycarbonyl-1-phthalazone-4-~-hydroxyacetic acid
(0.32 g) is added to 5 ml of water, to which is further added 0.04 g of p-toluene-
sulfonic acid. Thereafter, the reaction and the after-treatment are carried out
in the same manner as in Example 46, and there is obtained 0.20 g (yield 72~) of
the objective compound i.e. ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-
carboxylate.
m.p. 171.5-173C.
This prcduct perfectly coincides with otherwise synthesized authentic
sample in IR, N~R and W spectra.
Example 52
Toluene (10 ml) is added to 2.48 g (10.0 mmol) of 3,5-dimethyl-4-
- 39 -
ethoxycarbonylphthalic anhydride and 3.62 g (12.0 m~ol) of cyanomethylenetri-
phen~lphosphorane, and the mixture is reacted at rocm temperature overniyht with
stirring. qhe reaction mixture is concentrated under reduced pressure, and the
residue is subjected to silica gel column chrcmatoyraphy [Merck Silica Gel ~
70-230 mesh, 150 g; developed with benzene-ethyl acetate (20 : 1 v/v] to separ-
ate the two products having the relation of geametric isomer each other. The
fractions containing respective isomers are collected and concentrated under re-
duced pressure to obtain the followings:
(Z)-3-cyanomethylene-5,7-dimethyl-6-ethoxycarbonylphthalide 433 mg
(1.60 mmol), yield 16.0%, m.p. 108-109 &.
(E)-3-cyanamethylene-5,7-dimethyl-6-ethoxycarbonylphthalide 329 m~
(1.20 mmol), yield 12.0~, m.p. 135-136 & .
Example 53
(Z)-3-Cyanomethylene-5,7-dimethyl-6-ethoxycarbonylphthalide 0.10 g
(0.37 mmol) is dissolved into 3.0 ml of ethanol, to which is added 0.23 g (3.7
mmol) of 80% aqueous solution of hydrazine hydrate. m e mixture is heated under
reflux overnight. me reaction mixture is concentrated under reduced pressure
and the residue is recrystallized from ethanol. Thus, 0.65 g (0.23 mmol) of
4-cyanomethyl-6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone is obtained. Yield 62%.
m.p. 191-192&.
IR spectr~m: vmax (cm ) = 3160, 3050, 2950, 2260, 1730, 1650, 1605, 1278,
1247, 1153, 1122, 1040
NMR spectr~m (CDC13): ~ = 1.37 (t, 3H, J = 7.0Hz; OCH2CH-2)' 2.45, 2.82
(s, s, 3H, 3H; phen~l-CH3), 4.43 (s, 2H; -CH2CN), 4.46 (q, 2H, J =
7.0Hz; OC_2CH3), 7.68 (s, lH; phenyl-H), 12.15 (broad, lH; NH).
Example 54
Toluene (100 ml) is added to 12.40 g (50.0 mmol) of 3,5-dimethyl-4-
- 40 -
~ ,r
ethoxycarbonylphthallc anhydride and 22008 g (73.3 mmol) of cyanomethylenetri-
phenylphosphorane, and the mixture is reacted at room tem~erature overnight with
stirring. The reaction mlxture is conoentrat?d under reduced pressure, the
residue is dissolved into 250 ml of ethanol, 31.3 g (500 mmol) of 80% aqueous
solution of hydrazine hydrate is added thereto, and the resulting mixture is
heated under reflux overnight. After the reaction, the reaction mixture is con-
centrated under reduced pressure and the residue is separated and purified by
silica gel column chrcmatography [Merck Silica Gel ~ 70-230 mesh, 1.2 kg;
developed with toluene-ethyl acetate (3 : 1 v/v)]. Thus, 4.48 g (15.7 mmol) of
ethyl 4-cyanomethyl-6,8-dimethyl-1-phthalazone-7-carboxylate is obtained. Yield
31.4%.
m.p. 191-192C.
This product well coincides with the product of Example 53 in IR and
NMR spectra.
Example 55
Ethyl 4-cyanomethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (285 mg,
1.00 mmol) is dissolved into a solvent mixture comprising 2 ml of glacial aoe tic
acid and 1 ml of acetic anhydride, to which is added 0.70 g (4.4 mmol) of
bromine. The mixture is reacted at room temperature overnight with stirring.
The reaction mixture is diluted with 50 ml of chloroform and washed with cold
water. The chloroform layer is dried over with anhydrous sodium sulfate and
then conce~trated under reduced pressure. The residue is recrystallized from
10 ml of benzene, and there is obtained 278 mg (0.76 mmol) of ethyl 4-bromocyano-
methyl-6,8-dlmethyl-1-phthalazone-7-carboxylate. Yield 76%.
m.p. 197-199C.
Example 56
Ethyl 4-cyancmethyl-6~8-dimethyl-1-phthalazone-7-carboxylate (0.57 g,
- 41 -
~S~648
2~0 mmol) is dissolved into 6 ml of glacial acetic acid, to ~lich is added
0.40 g (2.5 mmol? of bromine. me mixture is reacted at room temperature over-
night with stirring. After the reaction, 0.36 g of 95% sulfuric acid is added
to the reaction mixture and heated at 80C for one hour. After heating, the
reaction mixture is cooled to room temperature, concentrated under reduced pres-
sure, the residue is dissolved in 200 ml of chloroform and then the solution is
washed with water. The organic layer is dried over with anhydrous sodium sul-
fate and concentrated under reduced pressure, and the residue is recrystallized
from 20 ml of chloroform. Thus, 0.65 g (1.7 mmol) of ethyl 4-(~-bromo-~-
carbamoylmethyl)-6,8-dimethyl-l-phthalazone-7-carboxylate is obtained. Yield 85%.
m.p. 209-211C (deo~mposition).
IR spectrum: vmax (cm ) = 3400, 3200, 3000, 2950, 1720, 1660, 1600, 1300,
1280, 1240, 1140, 1120, 1040
NMR spectr~m (DMSO-d6): ~ = 1.33 (t, 3H, J = 7.0Hz; OCH2CH3), 2.39, 2.76
(s, s, 3H, 3H; phenyl-CH3), 4.40 (q, 2H, J = 7.0Hz; OCH2CH3), 6.12
(s, lH; CHBr), 7.63 (s, 2H; CCNH2), 7.82 (s, lH; phenyl-H)I 12.70
(s, lH; NH)
Example 57
Ethyl 4-(~-bromo-~-carbamoyLmethyl)-6,8-dimethyl-1-phthalazone-7-
carboxylate (3.82 g, 10 mmol) is dissolved into 38 ml of n-propanol, to which is
added 19 ml of concentrated hydrochloric acid. The mixture is heated under re-
flux for 24 hours. The reaction mixture is concentrated under reduced pressure
to distil off the solvent and 5.0 ml of distilled water is added to the residue.
The deposited crystals are collected by filtration, washed with water and dried
to obtain 0.83 g (30 mmol) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-
7-carboxylate. Yield 30%.
A portion of the crystals obtained herein is recrystallized f~om
- 42 -
~!
6~8
aqueous ethanol. It well coincides with authentic sample in NMR, IR and W
spectra.
Example 58
Ethyl 4-cyanomethyl-6,8-dimethyl-1-phthalazone-7-~arboxylate (285 mg
10 mmol) is dissolved into 1 ml of 95% sulfuric acid with cooling and stirred at
rcom temperature for 5 hours to complete the reaction. The reaction mixture is
poured into crushed ice and the resulted precipitates are collected by filtra-
tion. It is recrystallized from aqueous ethanol~ and there is obtained 269 mg
(0.887 mmol) of ethyl 4-carbamoylmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate.
Yield 88.7%.
m.p. 248-258&.
IR spectrum: vmax (cm ) = 3420, 3300, 3180, 2950, 1730, 1670, 1653, 1620,
1603, 1280, 1250, 1200, 1150, 1125, 1038
NMR spectrum (DMSO-d6): ~ = 1.33 (t, 3H, J = 7.0Hz; OCH2CH3), 2.38, 2.77
(s, s, 3H, 3H; phenyl-CH3), 3.75 (s, 2H; C_2CaNH2), 4.42 (q, 2H, J =
7.0Hz; OCH2CH3), 7.05 (s, lH, the other H of CH2CON_2), 7.58 (s, 2H,
the other H of CH2CaNH2 and phenyl-H), 12.36 (s, lH, NH)
Example 59
Glaeial acetic aeid (4 ml) is added to 121 mg (0.40 mmol) of ethyl
4-carbamoylmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate, to which is added
67 mg (0.42 mmol) of bromine. m e mixture is reacted at room temperature over-
night with stirring. me reaction mixture is concentrated under reduced pres-
sure, the residue is dissolved in 50 ml of chloroform and washed with water.
me organic layer is dried over with anhydrous sodium sulfate and then concen-
trated under reduced pressure, and the residue is recrystallized from 5 ml of
chloroform. m us, 130 mg (0.34 mmol) of ethyl 4-(a-bromo-a-carbamoylmethyl)-6,8-
dimethyl-l-phthalazone~7-carboxylate is obtained. Yield 85%.
m.p. 209-211C (decomposition).
- 43 -
~'
115if~8
This produc-t well coincides with the prcduct of Example 56 in IR and
NMR spectra.
Example 60
Ethyl 4-cyanomethyl-6,8-dimethyl-1-phthalazone-7-carboxylate (285 mg,
1.00 mmDl) is added to a mixture comprising 2.0 ml of concentrated hydrochloric
acid and 2.0 ml of dioxane and heated under reflux overnight to complete the
reaction. me reaction mixture is concentrated under reduoe d pressure, water is
added to the residue, and the deposited crystals are collected by filtration,
washed with water and recrystallized from aqueous acetone. m us, 260 mg (0.856
mmol) of 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-7-aoetic ad d is obtained.
Yield 85.6%.
m.p. 162-163& (deccmposition with foaming).
m is product perfectly coincides with the product of Example 8 in IR
and NMR spectra.
Example 61
Ethyl 4-carbamoylmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(303 mg, 1.00 mmol) is added to 5.0 ml of 2 N hydrochloric acid and reacted for
5 hours while heating it under reflux. After the reaction, the reaction mixture
is cooled and the deposited crystals are collected by filtration, washed with
water and dried. Thus, 274 mg (0.901 mmol) of 6,8-dimethyl-7-ethoxycarbonyl-1-
phthalazone-4-aoetic acid is obtained. Yield 90.1~.
m.p. 162.5-163.5& (decomposition with foaming).
This prcduct well coincides with the product of Example 8 in IR and
NMR spectra.
Example 62
Ethyl 4-cyan~methyl-6,8-dimethyl-1-phthalazone-7-carboxylate (285 mg,
1.00 mmol) is added to a mixture comprising 6.0 ml of 2 N aqueous solution of
- 44 -
~S~
sodium hydroxide and 3.0 ml of n-propanol and the mixture is reacted overnight
under reflux. The L~action mixture is concentrated under reduoe d pressure to
distil off the solvent, water is added to the residue, pH of the aqueous mixtureis adjusted to l-2 with hydrochloric acid, and the deposited crystals are col-
lected by filtration, washed with water and recrystallized from aqueous acetone.Thus, 223 mg (0.733 mmol) of 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-
aoetic acid is obtained. Yield 73.3%.
m.p. 163-164C (decomposition with foaming).
This product well coincides with the product of Example 8 in IR and
NMR spectra.
Example 63
Ethyl 4-carbamoylmethyl-6,8-dimethyl-1-phthalazone-7-carboxylate
(303 m~, 1.00 mmol) is added to a mixture comprising 6.0 ml of 2 N aqueous solu-tion of sodium hydroxide and 3.0 ml of ethanol and heated under reflux overnight.
me reaction mixture is con oe ntrated under reduced pressure to distil off the
solvent, water is added to the residue, pH of the aqueous mixture is adjusted to1-2 with hydrochloric acid, the deposited crystals are aollected by filtration
and the crystals are recrystallized from aqueous acetone. Thus, 211 mg (0.695
mmol) of 6,8-dimethyl-7-ethoxycarbonyl-1-phthalazone-4-aoe tic acid is obtained.Yield 69.5%.
m.p. 163-164& (decomposition with foaming).
miS product well aoincides with the product of Example 8 in IR and
NMR spectra.
Example 64
Ethyl 4-(~-bromo-~-carbamoylmethyl)-6,8-dimethyl-l-phthalazone-7-
~rboxylate (535 mg) is dissolved in lO ml of glacial acetic acid. Then 574 mg
of anhydrous sodium acetate is added to the solution. The mixture is reacted
- ~5 -
~51648
for 12 hours under reflux. After the reaction, the reaction mixture is concen-
trated under reduoe d pressure to distil off the solvent. Water is added to the
residue and the deposited crystals are collected by filtration, washed with
water and dried. mus, 435 mg (yield 85.7~) of ethyl 4~ aoe toxy-~-c æbamoyl-
methyl)-6,8-dimethyl-1-phthalazone-7-carboxylate is obtained.
m.p. 210-212C.
Example 65
Ethyl 4-(~-aoetoxy-~- OE bamoylmethyl)-6,8-dimethyl-1-phthalazone-7-
OE boxylate (0.72 g) is dissolved into 10 ml of n-propanol, to which 5 ml of con-
centrated hydrochloric acid is added. me mixture is reacted for 19 hours underreflux. The reaction mixture is con oentrated under reduced pressure to distil
off the solvent. The residue is diluted with 2 ml of water and the deposited
crystals are collected by filtration, washed with water and dried. mus, 0.43 g
(yield 69~) of ethyl 6,8-dimethyl-4-hydroxymethyl-1-phthalazone-7-carboxylate is
obtained.
m.p. 173-175C.
mis product well coincides with otherwise synthesized product in IR,
NMR and W spectra.
- 46 -
