CA1076134A - Process for preparing phenylacetic acid ester derivatives - Google Patents
Process for preparing phenylacetic acid ester derivativesInfo
- Publication number
- CA1076134A CA1076134A CA267,690A CA267690A CA1076134A CA 1076134 A CA1076134 A CA 1076134A CA 267690 A CA267690 A CA 267690A CA 1076134 A CA1076134 A CA 1076134A
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- ether
- acid
- mixture
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to a process for preparing phenylacetic acid ester derivatives of the following general formula :
The present invention relates to a process for preparing phenylacetic acid ester derivatives of the following general formula :
Description
~(~76~3~
The present invention relates to a process for preparing novel phenylacetic acid esteT deriYatives of the general formula lA] :
:.
~CHCH2 ~ COOR
[A]
.' , '.
wberein R is selected from the group consisting of lower alkyl ~-(other than ethyl) and substituted lower alkyl, and R may be a hydrogen or methyl.
Detailed description-c of R in the general formula ~A] are given in the following. R is selected from the group oonsist-ing of (1) lower alkyl contai~ing up to 6 carbon atoms(other than ethyl), and
The present invention relates to a process for preparing novel phenylacetic acid esteT deriYatives of the general formula lA] :
:.
~CHCH2 ~ COOR
[A]
.' , '.
wberein R is selected from the group consisting of lower alkyl ~-(other than ethyl) and substituted lower alkyl, and R may be a hydrogen or methyl.
Detailed description-c of R in the general formula ~A] are given in the following. R is selected from the group oonsist-ing of (1) lower alkyl contai~ing up to 6 carbon atoms(other than ethyl), and
(2) the lower alXyl containing up to 6 carbon a~oms which is substituted with 1 ~o 3 substituents consisting of hydro-; ; xyl, h~logen, lower alkoxy, lower acyloxy, Iower alkoxy-carbonyl, hydroxy-lower alkoxy, di-lower alkylamino, cyclic amino, lower cycloalkyl, phenyl, substituted phenyl, tetra-hydrofuryl, pyridyl, substituted pyridyl and naphthyl.
~::
In the aforesaid substituted lower alkyl, typical examples of the su~stituents are as follows. Halogen may be chlorine, fluoTine, bromine or iodine. Lower alkoxy is methoxy, ethoxy or propoxy. Lower acyloxy is acetoxy or propionyloxy. Lower alkoxycarbonyl is methoxycarbonyl or ethoxycarbonyl. Hydroxy-lower alkoxy is hydroxyethoxy or hydroxypropoxy. Di-lower ~ .
,, , ~ .
:. . .
.
, '. ' ' ' ' , , .
.
~` 1076134 :: ~
alkylamino is dime~hylamino or diethylamino. Cyclic amino is morpholino, N-methylpiperazinyl, N-phenylpiperazinyl, N-benzyl-piperazinyl 9 N-(~-hydroxyethyl)piperazinyl, piperidyl or pyrroli-dinyl, Lower cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl ' "
or cyclohexyl. Substituted phenyl may be phenyl substltuted at '~
any position with 1 or 2 substitusnts consisting of halogen such as''chlorine, fluorine, bromine and iodine, lower alkyl such as methyl, ethyl and isobutyl, lower alkoxy such as methoxy and ' ' ' ethoxy, trifluoromethyl and nitro. Pyridyl is 2-pyridyl, 3-pyridyl or ~-pyridyl. Subs~tit~ted pyPidyI'may'be~'~pyridyl substi-tuted at any position with halogen such as chlorine, bromine an'd : . , .
iodine and methyl.
' The compounds obtained by the process of the present invention produce a high degree of analgetic, anti-pyretic and snti-inflammatory activities and little side effects on the gas-tro-intestinal tracts, when they are administered orally and ~ ~ ' - ~ .
topically. Therefore, they may be useful as oral and topical analgetics, antipyretics and anti-inflammatory agents.
Ad~enalcortical hormone preparations have been used as predom mant anti-inflammatory agents fo~ external use. However, ' ';
even when these preparations are applied topically, thier long-term application may often cause untoward side effects. Thus, the non-steroidal anti-inflammatory agents with low taxicity have been demanded for a long time. The present invention may offer the advantageous process for preparing the compounds which meet fully these demands.
The pres0nt invention relates to the' process for prepar-ing novel compounds of the aforesaid general formula [A] which - . . ~ - . ,. . ~ , - , , . ,., ,........... ,, . ,, .- .- , .. -: ,, -,, . , " ~ .. .. . . .
comprises reacting a compound of the general formula (I) :
,.
CHCH ~ CHX
( ) ,~
wherein R has the same meanings as defined in the aforesaid gene~al ~ormula ~A]; X is selected ~rom the group consisting of carboxyl, carbonic acid metal salt, haloformyl, lower alkoxy- -carbonyl, cyano, acid anhydride residue( ~o-Qc RH ~ CH2CH~cHH ).
wlth a compound of the general formula RY (~) wherein R has the same meanings as defined in the aforesaid general formul~a [A~, Y is selected from hydroxyl, halogen and organic sulf~onyloxy. ~ ~
The~process~of the present invention may be illustrated by the~following reaction scheme.
CHCh~ ~ CHX + RY ~ ~CHCH~ ~ CHCOOR
A]
~ ~ .
PNrther details of the above reaction schem0 are given in the following.
The starting material o the general ~ormula (I) where X
may be haloformy}(e.g.-COCl) is obtained by treating a p-isobutylphenylacetic acid derivative with a halogenizing agent, ,~.
. ~. :
. . .. . .
`~ ~
: ~ . , . . -, . :
: ' , .. .
)76134 and allowed to reac-t with an alcohol of the general formula (~) -in an unreactive organic solvent such as tetrahydrofuran, diglyme, dioxane, acetone,chloroform, benzene or toluene in the presence of a dehydrating agent such as pyridine, trimethylamine, triethyl-amine, potassium carbonate or sodium carbonate.
The starting material of the general formula (I) where X
may be carbonic acid metal salt(e.g.-COONa) is obtained by treating a p-isobutylphenylacetic acid derivative with an alkali metal, and allowed to react with an alkali halide of the general formula ~) in an organic solvent such as benzene, toluene, xylene, tetrahydrofuran, diglyme, dioxane, dimethylformamide or dimethylsulfoxide. The reaction proceeds smoothly at room temperature, and promoted by application of heating.
To a compound of the general formula (I) where X may be lower alkoxycarbonyl is added an alcohol of the general formula (~) in excess, and the mixture is heated at or in the vicinity of the boiling point of the solvent used either with or without adding a small amount of an alkali metal to produce ester interchange. PTeerred solvents are benzene, toluene and xylene.
The use of excess of the alcohol also serves for another pre-ferred solvent.
A compound of the general formula (I) where X may be an acid anhydride residue( ~O,~ ~H ~ CH~CH'CH ) an excess of alcohol of the general formula (~)by heating either with or without adding an acid catalyst. Por this reac tion, unreactive solvents may be used in some case.
A compound of the general formula (I) where X may be car-boxyl is reacted with an alcohol of the general formula (~) ,. . . .. . .
.. . . . . . . . . . . . . .
.. : . . . .
... . . . .. . . . . . .
.. , ,, : , , , . , ~:
. ' , . ' ,, . : ..
Under reflux in the presence of a dehydrating agent such as sul~u~ic acid, poly-phosphoric acid or p-toluenesulfonic acid in an organic solYent such as benzene-, toluene or xylene. The use of excess of the alcohol (~) also serves for the reaction solvent.
A compound of the general formula (I) where X may be cyano is heated with an alcohol of the general formula (~) in the presence of an acid catalyst(e.g. sulfuric acid).
Compound :
Some examples of the compound obtained by the process of the present invention are illustrated in Table I including their appearnace, boiling points and mass spectra(parent ion~.
L~
`: : :
: , :
~ ' , ;';
: :
: ~ ' .
.' ' ', ' . . ' ' ' , :' ' , ' .
--` 1076~34 Table I
. . . ., . .
Examples of the compounds of the general formula [A~ obtained by the present invention.
CHCH2 ~ CHCOOR [A]
_ ~ _ C~ound R' R Appearance ~ass spectra ;~ No. (~oiling point:C/mmHg) (Parent ion) : _ ' 1 CH3 -CH3 . Oil(90-92/0.5) 220 :: _ . , . _ _ 2 ,- -CH2CH2CH3 ~ (100-103/0.3) 248 _ . . . . _ ~ 3 " -CH~ccHH33 ~- ~91-92/0.5) 248 : _ .. ~ .
4 .. -CH2CH2CH2CH3 ,. ~97-98/0.1) 262 ~ _ _ __ ~ ~, S - -CH2CH~CH - ~84-87/0.1) 262 ~: . _ ~ .' ; 6 ..-~cH23scH3 - ~131-133/0.6) 290 _ . _ . ~ _ 7 ., -CH2CH2F ll ~110-111/1.0) 238 _ _ 8 ll -CH2CH2Br ll (118-120/0.1) 298 ~; ~ : _ :
9 ,l -CH2CF3 ll (73-74/0.12) 288 ' _ 1 0 ., -CH2CH2OH ll ~138-139/1.03 250 ~ ' _ _ _ _ ., 1 1 ll -CH2gHCH2OH ~l ~153-154/1.0) 280 1 2 .. -CH2OCH3 ll ~75-76/1.0) 250 _ _ 1 3 ll -CH2OC2Hs ~ ~118-119/1.0) 264 . . _ .. :.. - ,i ... .
.~. . . . .. ... . . . . .
. , . . :
.-; :, , -,: :" ''~
' . . ,:
: .
1~76~34 .
Compound R RAppearance Mass spectra No. (Boiling point:C/mmHg) ~Parent ion) 1 4 CH3 -CH2CH20CH3 Oil (108-110/0.7) 264 _ .
1 5 " -CH2CHj20C2Hs "tl26-127/l.o) 278 1 6 .l -CH2CH20CH2CH20H .l(140-142/0.15) 294 _ _ i.
1 7 .l -CHzOCOCH3 ,l 278 _ _ _ , : 1 8 ,. -CH2CH20COCH3 ~(120-122/0.1) 292 : _ .
~ 1 9 " -CH2COOC2Hs . ll(123-124/0.23) 292 __ .
~;; :2 0 ll -CH2 ~ : ~(109-111/1.0) 260 _ .
2~1 ., -CH2 ~ ~~108-110/0.1) 296 ~::: . . . . . ._ Z 2 ,l -CH2 ~ ~.(145-147/0.5) 330 _ Cl - _ 2 3 ,l -CH2- ~ ll (148-149/0.18) 330 _ : I 2 4 ~ -CH2 ~ Cl ,l (153-155/0.5~ 330 _ F
~: ~ 2 5 " -CH2 ~ " (136-137/0.2) 314 . _ F __ _ _ _ : 2 6 ll -CH2 ~ ll (143-144/0.2) 314 _ ~:2 7 ll -CH2 ~ F ll(118-120/0.2) 314 ~:~ . ., 2 8 ll -CH2 ~ CF3 "(142-145/0.8) 364 . CH
2 9 ll -CH2 ~ "(145-148/0.28) 310 CHg
~::
In the aforesaid substituted lower alkyl, typical examples of the su~stituents are as follows. Halogen may be chlorine, fluoTine, bromine or iodine. Lower alkoxy is methoxy, ethoxy or propoxy. Lower acyloxy is acetoxy or propionyloxy. Lower alkoxycarbonyl is methoxycarbonyl or ethoxycarbonyl. Hydroxy-lower alkoxy is hydroxyethoxy or hydroxypropoxy. Di-lower ~ .
,, , ~ .
:. . .
.
, '. ' ' ' ' , , .
.
~` 1076134 :: ~
alkylamino is dime~hylamino or diethylamino. Cyclic amino is morpholino, N-methylpiperazinyl, N-phenylpiperazinyl, N-benzyl-piperazinyl 9 N-(~-hydroxyethyl)piperazinyl, piperidyl or pyrroli-dinyl, Lower cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl ' "
or cyclohexyl. Substituted phenyl may be phenyl substltuted at '~
any position with 1 or 2 substitusnts consisting of halogen such as''chlorine, fluorine, bromine and iodine, lower alkyl such as methyl, ethyl and isobutyl, lower alkoxy such as methoxy and ' ' ' ethoxy, trifluoromethyl and nitro. Pyridyl is 2-pyridyl, 3-pyridyl or ~-pyridyl. Subs~tit~ted pyPidyI'may'be~'~pyridyl substi-tuted at any position with halogen such as chlorine, bromine an'd : . , .
iodine and methyl.
' The compounds obtained by the process of the present invention produce a high degree of analgetic, anti-pyretic and snti-inflammatory activities and little side effects on the gas-tro-intestinal tracts, when they are administered orally and ~ ~ ' - ~ .
topically. Therefore, they may be useful as oral and topical analgetics, antipyretics and anti-inflammatory agents.
Ad~enalcortical hormone preparations have been used as predom mant anti-inflammatory agents fo~ external use. However, ' ';
even when these preparations are applied topically, thier long-term application may often cause untoward side effects. Thus, the non-steroidal anti-inflammatory agents with low taxicity have been demanded for a long time. The present invention may offer the advantageous process for preparing the compounds which meet fully these demands.
The pres0nt invention relates to the' process for prepar-ing novel compounds of the aforesaid general formula [A] which - . . ~ - . ,. . ~ , - , , . ,., ,........... ,, . ,, .- .- , .. -: ,, -,, . , " ~ .. .. . . .
comprises reacting a compound of the general formula (I) :
,.
CHCH ~ CHX
( ) ,~
wherein R has the same meanings as defined in the aforesaid gene~al ~ormula ~A]; X is selected ~rom the group consisting of carboxyl, carbonic acid metal salt, haloformyl, lower alkoxy- -carbonyl, cyano, acid anhydride residue( ~o-Qc RH ~ CH2CH~cHH ).
wlth a compound of the general formula RY (~) wherein R has the same meanings as defined in the aforesaid general formul~a [A~, Y is selected from hydroxyl, halogen and organic sulf~onyloxy. ~ ~
The~process~of the present invention may be illustrated by the~following reaction scheme.
CHCh~ ~ CHX + RY ~ ~CHCH~ ~ CHCOOR
A]
~ ~ .
PNrther details of the above reaction schem0 are given in the following.
The starting material o the general ~ormula (I) where X
may be haloformy}(e.g.-COCl) is obtained by treating a p-isobutylphenylacetic acid derivative with a halogenizing agent, ,~.
. ~. :
. . .. . .
`~ ~
: ~ . , . . -, . :
: ' , .. .
)76134 and allowed to reac-t with an alcohol of the general formula (~) -in an unreactive organic solvent such as tetrahydrofuran, diglyme, dioxane, acetone,chloroform, benzene or toluene in the presence of a dehydrating agent such as pyridine, trimethylamine, triethyl-amine, potassium carbonate or sodium carbonate.
The starting material of the general formula (I) where X
may be carbonic acid metal salt(e.g.-COONa) is obtained by treating a p-isobutylphenylacetic acid derivative with an alkali metal, and allowed to react with an alkali halide of the general formula ~) in an organic solvent such as benzene, toluene, xylene, tetrahydrofuran, diglyme, dioxane, dimethylformamide or dimethylsulfoxide. The reaction proceeds smoothly at room temperature, and promoted by application of heating.
To a compound of the general formula (I) where X may be lower alkoxycarbonyl is added an alcohol of the general formula (~) in excess, and the mixture is heated at or in the vicinity of the boiling point of the solvent used either with or without adding a small amount of an alkali metal to produce ester interchange. PTeerred solvents are benzene, toluene and xylene.
The use of excess of the alcohol also serves for another pre-ferred solvent.
A compound of the general formula (I) where X may be an acid anhydride residue( ~O,~ ~H ~ CH~CH'CH ) an excess of alcohol of the general formula (~)by heating either with or without adding an acid catalyst. Por this reac tion, unreactive solvents may be used in some case.
A compound of the general formula (I) where X may be car-boxyl is reacted with an alcohol of the general formula (~) ,. . . .. . .
.. . . . . . . . . . . . . .
.. : . . . .
... . . . .. . . . . . .
.. , ,, : , , , . , ~:
. ' , . ' ,, . : ..
Under reflux in the presence of a dehydrating agent such as sul~u~ic acid, poly-phosphoric acid or p-toluenesulfonic acid in an organic solYent such as benzene-, toluene or xylene. The use of excess of the alcohol (~) also serves for the reaction solvent.
A compound of the general formula (I) where X may be cyano is heated with an alcohol of the general formula (~) in the presence of an acid catalyst(e.g. sulfuric acid).
Compound :
Some examples of the compound obtained by the process of the present invention are illustrated in Table I including their appearnace, boiling points and mass spectra(parent ion~.
L~
`: : :
: , :
~ ' , ;';
: :
: ~ ' .
.' ' ', ' . . ' ' ' , :' ' , ' .
--` 1076~34 Table I
. . . ., . .
Examples of the compounds of the general formula [A~ obtained by the present invention.
CHCH2 ~ CHCOOR [A]
_ ~ _ C~ound R' R Appearance ~ass spectra ;~ No. (~oiling point:C/mmHg) (Parent ion) : _ ' 1 CH3 -CH3 . Oil(90-92/0.5) 220 :: _ . , . _ _ 2 ,- -CH2CH2CH3 ~ (100-103/0.3) 248 _ . . . . _ ~ 3 " -CH~ccHH33 ~- ~91-92/0.5) 248 : _ .. ~ .
4 .. -CH2CH2CH2CH3 ,. ~97-98/0.1) 262 ~ _ _ __ ~ ~, S - -CH2CH~CH - ~84-87/0.1) 262 ~: . _ ~ .' ; 6 ..-~cH23scH3 - ~131-133/0.6) 290 _ . _ . ~ _ 7 ., -CH2CH2F ll ~110-111/1.0) 238 _ _ 8 ll -CH2CH2Br ll (118-120/0.1) 298 ~; ~ : _ :
9 ,l -CH2CF3 ll (73-74/0.12) 288 ' _ 1 0 ., -CH2CH2OH ll ~138-139/1.03 250 ~ ' _ _ _ _ ., 1 1 ll -CH2gHCH2OH ~l ~153-154/1.0) 280 1 2 .. -CH2OCH3 ll ~75-76/1.0) 250 _ _ 1 3 ll -CH2OC2Hs ~ ~118-119/1.0) 264 . . _ .. :.. - ,i ... .
.~. . . . .. ... . . . . .
. , . . :
.-; :, , -,: :" ''~
' . . ,:
: .
1~76~34 .
Compound R RAppearance Mass spectra No. (Boiling point:C/mmHg) ~Parent ion) 1 4 CH3 -CH2CH20CH3 Oil (108-110/0.7) 264 _ .
1 5 " -CH2CHj20C2Hs "tl26-127/l.o) 278 1 6 .l -CH2CH20CH2CH20H .l(140-142/0.15) 294 _ _ i.
1 7 .l -CHzOCOCH3 ,l 278 _ _ _ , : 1 8 ,. -CH2CH20COCH3 ~(120-122/0.1) 292 : _ .
~ 1 9 " -CH2COOC2Hs . ll(123-124/0.23) 292 __ .
~;; :2 0 ll -CH2 ~ : ~(109-111/1.0) 260 _ .
2~1 ., -CH2 ~ ~~108-110/0.1) 296 ~::: . . . . . ._ Z 2 ,l -CH2 ~ ~.(145-147/0.5) 330 _ Cl - _ 2 3 ,l -CH2- ~ ll (148-149/0.18) 330 _ : I 2 4 ~ -CH2 ~ Cl ,l (153-155/0.5~ 330 _ F
~: ~ 2 5 " -CH2 ~ " (136-137/0.2) 314 . _ F __ _ _ _ : 2 6 ll -CH2 ~ ll (143-144/0.2) 314 _ ~:2 7 ll -CH2 ~ F ll(118-120/0.2) 314 ~:~ . ., 2 8 ll -CH2 ~ CF3 "(142-145/0.8) 364 . CH
2 9 ll -CH2 ~ "(145-148/0.28) 310 CHg
3 0 .. -CH2 ~ "(119-121/0.2) 310 __ 3 1 i -CH2 ~ CH3 ll(139-140/0.1) 310 i .: ', ', ' : ' ' ~ , ' '' . ' ' :
' , : . . ..
:~ '. ' ' , . ; . . . ..
.
~1~76~3~ -Co~pound R R Appearance Mass spectra No. _ _ _ (~oilmg point:C/mmHg) ~Parent ion) 3 2 CH3 -CH2 ~ OCH3 Oil ~149-151/0.1) 326 _ _ _ _ . .
3 3 " -CH2Cl ~ ~ tl53-155/0.1) 364 Cl _ _ 3 4 -CH2CH2 ~ j .- (142-144/0.18) 310 3 5 ll -CH2CH2 ~ ll 328 3 6 ll -CH~CH2 ~ F ,. 328 _ ._ _ _ , , 3 7 .. -CH2CH2 ~ CH3 .. (155-160/0.2) 324 CH3 ,CH3 3 8 ll -CH2CH ~ CH2CH~cH " ~162-165/0.2) 380 . 3 3 9 ll -CH2CH2N~CcHH3 " (133-136/1.0) 277 _ _ .
' , : . . ..
:~ '. ' ' , . ; . . . ..
.
~1~76~3~ -Co~pound R R Appearance Mass spectra No. _ _ _ (~oilmg point:C/mmHg) ~Parent ion) 3 2 CH3 -CH2 ~ OCH3 Oil ~149-151/0.1) 326 _ _ _ _ . .
3 3 " -CH2Cl ~ ~ tl53-155/0.1) 364 Cl _ _ 3 4 -CH2CH2 ~ j .- (142-144/0.18) 310 3 5 ll -CH2CH2 ~ ll 328 3 6 ll -CH~CH2 ~ F ,. 328 _ ._ _ _ , , 3 7 .. -CH2CH2 ~ CH3 .. (155-160/0.2) 324 CH3 ,CH3 3 8 ll -CH2CH ~ CH2CH~cH " ~162-165/0.2) 380 . 3 3 9 ll -CH2CH2N~CcHH3 " (133-136/1.0) 277 _ _ .
4 0 ll C H " (129-130/1.0) 305 :
4 1 'l -CH2CH2CH2N/CcHH3 ~ tll5-117/l.o) 291 ~: ~ _ __. _ _ _. ~ , 4 2 ll -CH2CH2-N 3 " (128-131/1.0) 319 __ _ . ., 4 3 ll -CH2CH2-NN-CH3 " (130-135/1.0) 332 . _ __ ~ ~ 4 4 ll -CH2 ~ " (138-140/0.15) 297 _ _ . _ 4 5 ,l -CH2 ~ " tl38-139/l.o) ~ 297 _ . _ _ 4 6 ll -CH2 ~ N " (140-142/0.18) 297 . _ _ 4 7 ll -CH2 ~ " (142-145/0.1) 331 Cl ~ - .
4 8 ll -CH2CHz ~ " (114-llS/0.3) 311 _ _.__ ___ _ 4 9 -CH2 ~ " (109-110/1.0) 290 __ __... _. . . _ _ :-- . . . . -. , . : ' , , ' . .~:.
:: i , ; ., , , .. " .... ..
. . - ,................. . . . .
.
107~34 C~ound I R _ Appearance IMass spect~a No. l i ~Boiling point:C/mmHg) tParent ion)~ i colorless needles 360
4 1 'l -CH2CH2CH2N/CcHH3 ~ tll5-117/l.o) 291 ~: ~ _ __. _ _ _. ~ , 4 2 ll -CH2CH2-N 3 " (128-131/1.0) 319 __ _ . ., 4 3 ll -CH2CH2-NN-CH3 " (130-135/1.0) 332 . _ __ ~ ~ 4 4 ll -CH2 ~ " (138-140/0.15) 297 _ _ . _ 4 5 ,l -CH2 ~ " tl38-139/l.o) ~ 297 _ . _ _ 4 6 ll -CH2 ~ N " (140-142/0.18) 297 . _ _ 4 7 ll -CH2 ~ " (142-145/0.1) 331 Cl ~ - .
4 8 ll -CH2CHz ~ " (114-llS/0.3) 311 _ _.__ ___ _ 4 9 -CH2 ~ " (109-110/1.0) 290 __ __... _. . . _ _ :-- . . . . -. , . : ' , , ' . .~:.
:: i , ; ., , , .. " .... ..
. . - ,................. . . . .
.
107~34 C~ound I R _ Appearance IMass spect~a No. l i ~Boiling point:C/mmHg) tParent ion)~ i colorless needles 360
5 0 -CH3 -CH2CH2 ~ 52-54C* _ ¦
5 1 H -CH2CF3 Oil ( 78-79/1.0) 274 5-2 ll-CH2CH2OH .. (115-117/1,0) 236 , .,~
5 3 ,l-CH2C,HCH2OH .l 266 _ _ _ 5 4 ll -CH20CH3 .. (90-91/0.15) 236 ~: __ _ . _ I ~5 5 ,.-CH2OC2Hs . .. (116-118/1.0) 250 5 6 ll-CH2CHIOCH3 .. (97-98/1.0) ¦ 250 _ _ . _ 5 7 ll-CH2CH2OC2Hs .-(108-110/1.0) 264 :
5 8 ll-CH2CH20COCH3 .l(126-128/1.0) ~ 278 _ _ _ _ 5 9 :" -CH2 ~ ¦ .-(124-126/1.0) 282 ~: Cl - . . _ _
5 1 H -CH2CF3 Oil ( 78-79/1.0) 274 5-2 ll-CH2CH2OH .. (115-117/1,0) 236 , .,~
5 3 ,l-CH2C,HCH2OH .l 266 _ _ _ 5 4 ll -CH20CH3 .. (90-91/0.15) 236 ~: __ _ . _ I ~5 5 ,.-CH2OC2Hs . .. (116-118/1.0) 250 5 6 ll-CH2CHIOCH3 .. (97-98/1.0) ¦ 250 _ _ . _ 5 7 ll-CH2CH2OC2Hs .-(108-110/1.0) 264 :
5 8 ll-CH2CH20COCH3 .l(126-128/1.0) ~ 278 _ _ _ _ 5 9 :" -CH2 ~ ¦ .-(124-126/1.0) 282 ~: Cl - . . _ _
6 0 ,. -CH2 ~ ~-~145-147/1,0) 316 : ~: ._ _ 6 1 ll -CH2 ~ Cl ll(140-142/1.0) 316 , ~ _ ~ .
6 2 ll -CH2 ~ ll 300 I _ ~ 6 3 ll -CH2 ~ P I " ! 300 __ _ _ ; ~ 6 4 ll -CH2 ~ CH3 ll 296 : 6 5 ¦ "-CH2 ~ OCH3 ll 312 . _ 6 6 ,. -CH2 ~ ll (90-91/1.0) 350 I I Cl _ _ _ _ 6 7 ..-CH2CH2-N/CcH3 .l(110-111/1.0) 263 . _ _ _ _ *Only this value represents the mel~in~ point.
~, .~ . . ' -, ' ' ' . ' '", :: ''. . ' ~' ' . :
' :' ',''. :' '', , ''',' ' '. , " ., ~,,..: ' '', ','. ',' ,, . .:.. ' ', '. ',, ',, ''' :. ".:' . ' '' .' :
. ~n76l34 , ~ - --Compa~ R R Appearance Mass spectra !
No, i ~ (Boiling point:C/mmHg) (Parent ion) ¦
6 8 ~ -CH2CH2 N~C2Hs Oil (115-117/1.0) 291 6 9 " -CH2CH2CH2-N(CH3 ~(110-111/1.0) 277 . _ _ 1 0 " -CH2CH2-N~_,O ~(109-110/1.0) 305 . _ _ __
6 2 ll -CH2 ~ ll 300 I _ ~ 6 3 ll -CH2 ~ P I " ! 300 __ _ _ ; ~ 6 4 ll -CH2 ~ CH3 ll 296 : 6 5 ¦ "-CH2 ~ OCH3 ll 312 . _ 6 6 ,. -CH2 ~ ll (90-91/1.0) 350 I I Cl _ _ _ _ 6 7 ..-CH2CH2-N/CcH3 .l(110-111/1.0) 263 . _ _ _ _ *Only this value represents the mel~in~ point.
~, .~ . . ' -, ' ' ' . ' '", :: ''. . ' ~' ' . :
' :' ',''. :' '', , ''',' ' '. , " ., ~,,..: ' '', ','. ',' ,, . .:.. ' ', '. ',, ',, ''' :. ".:' . ' '' .' :
. ~n76l34 , ~ - --Compa~ R R Appearance Mass spectra !
No, i ~ (Boiling point:C/mmHg) (Parent ion) ¦
6 8 ~ -CH2CH2 N~C2Hs Oil (115-117/1.0) 291 6 9 " -CH2CH2CH2-N(CH3 ~(110-111/1.0) 277 . _ _ 1 0 " -CH2CH2-N~_,O ~(109-110/1.0) 305 . _ _ __
7 1 " -CH2CH2-N~_,N-CH 3 ~ 318 :
. . ., ._ . _ , ~
7 2 _ -CN ~ "(103-104/1.0) Z83 ~: 7 3 ,. -CH2 ~ . "(142-145/1.0) 283 _ _ _ _ _ ...
7 4 " -CH2 ~ "(106-108/1.0) 283 . . . .
7 5 " -CH2Gl ~ ~~150-153/1.0) 317 ; .
~ . _ ., ~ 7 6 -CH2 ~(73-75/0.15) 276 : '~
;
, : ~ . . . ~ . .. .
.. .
- - , ' , ' ' ' ,. -, ,, ', ' .,, ;' : ' , ~ , " ." "' . ,~ ' - , ~L07613q~
All of the compounds prepared by the process o the pre-sent invention were firs~ tested for their acute toxicities, and subsequently for their pharmacological ac~ivities such as anti-in~lammatory and analgetic activity. It is fount that certain of the compounds preparet by the process of the present inven-tion have shown a high degree of pharmacological activities with low toxicity. Especially, topical application of the said com-pounds h~s produced a higher anti-inflammatory potency than that of ibuprofen. The testing methods are described in the following, and the results are summarized in Table ~ .
(1) Acute toxicity Each test compound suspended in O.S % tragacanth-saline was administered intraperitoneally or orally to male mice of dd-strain(body weight 16-24 g). The lethal dose was estimated from the death of animals 72 hours following administration.
~2) Anti-inflammatory activity for oral route A group of five male rats of Wistar-strain(body weight 100-150 g ) were orally given each test compound suspended in O.S % tragacanth-saline. After 30 minutes 0.5-1.0 % carrageenin suspended in the water for injection was injected subcutaneously to a hind paw. After 3 hours the carrageenin adema was measured by volume, and the percent inhibition was determined with respect to the results for the control animals. Por comparison, the percent inhibition o~ each test compound prepared by the process of the present invention was divided by that of the reerence compound, ibuproen t2-(p-isobutylphenyl)propionic acid],to give the relative inhibition, which is included in Table ~ . The mean percent inhibition o~ ibuprofen was 37.4 % at a dose of 50 mg/kg .... ., : . ,, ,, , ., ,, . ,- . . .... . . .. .. .. .. . .
and 33.5 % at lO mglkg.
(3) Anti-inflamma~ory activity for ~opical rou~e The dorsal skin ef male rats of Wistar-straintb~dy weight :
about 100 g) were depilated. Carrageenin suspension was injected intra-dermally at a dose of 250~/0.05ml/site. The filter paper (size : 2.3 cm in diameter) was impregnated with 1 % test com-pound dissolved in polyethylene glycol 300. Immediately after injection, the filter paper containing 125.2 + 18.0 mg of the polyethylene glycol was applied on the injected site. After 3 hours, 1 % pontamine sky blue solution was injected intrave-nously at a dosc of 0.5 ml/kg. After further 3 hours, the animals were sacrificed and their dorsal skin were removed to measure the area of leakage of the pigment. The percent inhibition was determined with respect to the resul~s for the control animals.
Fo~ comparison, the percent inhibition of each test compound prepared by the process of the present invention was dlvided by ~that of the reference compound, ibuprofen, to giva the relative inhibition. The mean percent inhibition of ibuprofen was 23,8 ~.
(4) Analgetic activity Each test compound suspended in 0.5 % tragacanth-saline was orally administered to dd-strain micetbody weight : 18-20 g ).
After one hour 0.6 % acetic acid solution was injected intra-peritoncally in a volume of O.lml/10 g. The writhing syndrome was observed for 10 minutes from 30 minutes after injection, and S0 % analgetic ef~ective dose(~Ds0) and its 95 % confidence limit were calculated by Litchfield-Wilcoxon's method.
; . . ..
~(97~;13~
Table ~
Pharmacological Ef~cts and Acute Toxici~y o~ tha Object Com-pound, Ph~nylace~ic Acid Derivatives obtained by the Present Inve~ion :
_. . . _ . _ anti-in1ammator I analgetic acute ~ffect effect toxicity Standard compound oral topica~ EDso (mg/kg) 50 10 ~mg/kg) g/kg mg/kg (95%C.L.) oral . ~ _ ibupro~en l 1.0 1.0 1.0 45 8 1000-2000 .
_ _ _ _ Object Compound of anti-infLammator I analgetic acute General Formula [A] effect effect toxicity R' H3C\ fi-~ I BDso (mg/kg) :~ CHCH2~Y ~CHCOOR
H3C/ ~ ~mg/kg) oral ~A] oral topical ~ . ~
:~ R R 50 10 (95%C.L.) m~/k~ mg/kg _ _ .
::~ CH3 -CH~ 1.4 0.8 3.5:(107.3 111.1)~2000 _ ~ ~-CH2CH2CH 3 1.1 0.7 3.2 192 3 ~2000 :;: . . . . ~ __ ~ : -~CH2~sCH3 1.2 ~ 13, 5(197,9 231.9) >2000 . _ : _ -CH2CP3 1.3 0.8 3.6(I29.4 139.8)1000-2000 : .- -CH2CH2OH 1.0 0.S 1.9(148.8-161.0)~2000 _ ~ _ , _ , '.
-CH28HCH2OH 0,9 1.1 142.9 1000-2000 . _ , _. .':: ' .. -CH2OCH3 1.2 1.0 2.5(145.1 203.3)500-1000 ~ _.
-CH2OC2Hs 1.0 1.3 2.8(151.8-158.0)~2000 __ _ ~ .
L_____ -CH2CH20CH3 1.20.4 1.2 405.51000-2000 :.
13 :
,: : : :....... . ,: , , :, ,`,. , . , . : ~ .. . ..
.. . . . .. ... . . . . . . . . . .
... . . . . . .. . .. .. . . . ...
. : :, . . , . . , , " . .. . . .. . .
1~)76~34 I .
anti-inflammatory ¦ analgetic acute . .
. effect effect toxicity R Roral ¦topical EDs o (mg/kg) 50 10 1 (mg/kg) mg/kg mg/kg (95 % C . L . ) ora 1 CH3 -CH2CH20C2Hs 0.9 O. 7 1.2 (130 0 181 2) 1>2000 . l .. -CH2CH20C:H2CH20H 0.9 2.3 (143.3 158 7~ ¦>2000 : i -I
~ -CH20COCH3 0.9 0.9 _ _ " : -CH2CH20COCH3 1.1 0.7 2.2(285.9-329.3) >2000 _ _ _ 1. -~CH2COOC2Hs O.7 O. 5 1.9~ 146 3 - 214.3) > 2000 . , .
~ -CH2 ~ 1 1. 6 O .8 3.7( 98.6 108.0) 2000 _ . .
: -CH2 ~ O.9 O. 7 3.1(114.3 - 122.3) ~ 2000 ~ ~ Cl~ 1.0 0. S2. S( 3 7.1 65. 7 ) > 2000 :: :
:~ : ~ ,. -CH2- ~ Cl 1.O :O. 52.8 486 4 >2000 -- -CH2 ~ 1.7 1.6 ~( 183.2 220.6) '~5 ~ : -CH2 ~ 1.7 0.8 0.9(619.7 - 648.1) 1~ . ..
~:~ : ll -CH2 ~ F 1.2 1.1 ~; -- -CH2 ~ CH3 1.5 1.7 1.9¦(190.1- 269.2) --I - CH2 ~OCH 3 1.4 0.8 I Z .3¦ (203.2 - 236.4) L ~ -CH ~ ~ 1.O 0.6 L~ ( 70.9 88.3 ) i~
~ -CH2CH2N/cH3 ¦ 1.2 L~ Z, o 53 7 1000-2000 , . .
:-:, .. .. .. ,. - : . ,. . :
- ~ . .. . . . . - :: , . .. . , ~ .. ~. . . .
- . . .. ... .. . .. . .
... , .-: ,, ,, . : . . . . . .. . . .
.. . , , . . . :
.. ~ . . . . .. .
1(~7~134 _ . . . .
anti-inflammatory analgetic acut~
. effect effect toxicity , R R oral topical ED 5 D (mg/kg) 50 10 (mg/kg) . mg/kg mg/kg (95tC.L.) oral _ _ CH3 -CH2CH2N'C2H5 0.9 1.2 3.0 317.7 500-1000 _ ~ ll -CH2CH2GH2N~CcH3 1.1 0.7 2.2 ( 24.7 35.1 ) S00-1000 :
. - ........ . _ " -CH2CHi-N O 0.9 0.7 1.6 tl49.3 159.l) 1000-2000 "; -CU2CH2-N N-CH ¦ 1.1 1.0 2.5 ~ 19.8 43.4 ) 1000-2000 ~ _.. . . . .,. ., .. . . . . - --................... = _ : -CH2 ~ 1.8 0.7 4.0 ( 32.5 103.1) 1000-2000 :~ ~ ll -CH2 ~ 1.4 1.0 1.7 ( 26.2 36.2 ) 1000-2000 :: : l _ : ~ " -CH2 ~ 1.2 1.0 2.7 87.1 >2000 . . _ _ l " -CH2 ~ 2.5 0.8 1.8 762.0 >2000 Cl _ ;: _ -CHI ~ 0.9 0.6 3.1 ( 56.0 127.2) 1 1000-2000 : ". '"
~ , :
,~
~:
: ~ .' ,' ~
':'. .
, .. , . .... ... , .. , ... .. . , , . . ~ , . .. . . . . ...
... . .. . . . . .. . .
- :-, ., ; , . :. . , , . , : .
:. .,: . . . . .. . . , , , , ~, . . . . . .
~761~
Some of the preferred embodiments of the present invention are disclosed in the following examples. ~ -Example A mixture of 3.3 g of 2-(p-isobutylphenyl) propicnic acid sodium salt, 2.3 g of dimethylaminoethyl chloride and 30 ml of ~
benzene was refluxed for 12 hours. A solid mass produced was `~-filtered of, and the benzene was distilled away from the filtrate ~- -under reduced pressure to leave an oily residue. This residue was distilled under reduced pressure to give 3.5 g of 2-(p-isobutyl-phenyll propionic acid dimethylaminoethyl ester as a colorless oil, .
boiling at 133-136c/lmmHg. Analysis-calculated for C17H27N02 C, 73.6I~; H, 9.81; N, 5.05. Found: C, 73.50; H, 9.72;
N, S.02O The infrared spectrum showed strong C=0 absorportion at 1730 cm 1 characteristic for ester Mass spectrum: parent ion 277 m/e.
Example 2 ..
.
~ ~ A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethyl-.,. .
~ ~pyridine was heated at 65-70C for 10 hours. To this mixture `
".
was added 3.8 g of 2-(p-isobutylphenyl) propionic acid methyl euter, and the whole was heated at 95-100C for 8 hours. After cooling to room tempe~ature, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether was distilled away from the extract to leave a re~idue. The residue was passed through a column of sîlica gel, and the adsorbate was eluted with chloroform. The eluates were freed of chloro-form in vacuo to give 2.9 g of 2-(p-isobutylphenyl) propionic acid-3-pyridylmethyl ester as a colorless oil. The infrared spectrurn showed strong C=0 absorption at 1730 cm~l characteri~tic for ester. Mas~ spectrum: parent ion 297 m~e.
, , ~ ,, .
107613~
Example 3 To a mixture of 2.28 g of 2-(p-isobutylphenyl)propionic acid sodium salt in 20 ml of dimethylformamide was added 2.52 g of benzyl chloride and the whole was heated at 90 C for 3 hours.
After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether and the extract was dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.57 g of 2-(p-isobutyl-phenyl)propionic acid benzyl ester as a colorless oilj boiling .
at 108-110C/O.lmmHg. Analysis- Calculated for C20H2402 :
C,~ 81.04 ; H, 8.16. Found : C, 80.92 ; H, 8.02.
Example 4 ;; To a mixture of 2.24 g of 2-(p-isobutylphenyl)propionic acid chloride and 2.10 g of p-methoxybenzyl alcohol in 20 ml ;;
` ~of~tetrahydrofuran was added 1.50 g of triethylamine under :
cooling and the whole was stirred or 2 hours. Ater the reaction was complete, an insoluble matter produced was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue thus obtained was added water and the resulting mixture was extracted with ether. The ether layer separated was washed with succes-sive, 5 % sodium carbonate solution, 5 % hydrochloric acid solution and water, and then dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.81 g of 2-(p~isobutyl-,~
... . .. . . ..
.. .. .
. .
~` 10~6i34 phenyl)propionic acid-p-methoxybenzyl ester as a colorless oil, boiling a~ 149-151C/O.lmmHg. Analysis- Calculated for C2lH2603 : C, 77.27 ; H, 8.03. Found : C, 77.11 ; H, 8.12.
Example 5 A mixture of 4.12 g of 2-(p-isobutylphenyl)propionic acid, lS ml of 2,2,2-trifluoroethyl alcohol and 4.9 g of concentrated sulfuric acid was heated at 100 C for 12 hours. After the reaction was complete, the mixture was poured into ice-water and the resulting mlxture was extracted with ether. The ether layer separated was washed sufficiently with successive S ~
sodium carbonate solution and water, and dehydrated. The ether was removed by distillation to give an oily product. Distilla-tion of the product in vacuo yielded 4.95 g of 2^(p-isobutyl-phenyl)propionic acid-2,2,2-trifluoroethyl es*er as a pale yellow oil, boiling at 73-74C/0.12mmHg. Analysis- Calculated for ClsHlgF302 : C, 62.48 ; H, 6.64. Found : C, 62.31 ; H, 6.61.
Example 6 A mixture of 0.05 g of sodium in 20 ml of cyclopropylmethyl alcohol was heated at 50 C for S hours. To the mixture was added 2.2 g of 2-(p-isobutylphenyl)propionic acid methyl ester and the whole was refluxed for 10 hours. After the reaction - was completed, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water.
The resulting mix~ure was extracted with ether, and the extract was washed sufficiently with water and then dehydrated. The ether;was removed by distillation to leave a residual oily product.
' .
.. . . .
, , . ' ~ :
., , ... ~ .
, 11)76134 , This product was then distilled under reduced pressure to yield 1.38 g of 2-~p-isobutylphenyl)propionic acid cyclopropyl-methyl ester as a colorless oil, boiling at lO9-111C/lmmHg.
Analysis - Calculated for C~?H~402 : C, 78.42 ; H, 9.29.
Found : C, 78.19 ; H, 9.22.
Example 7 A mixture of 3.0 g of 2-(p-isobutylphenyl)propionic acid anhydride, 3.8 g of 2,2,2-trifluoroethyl alcohol and 0.5 cc of ;-~a ~ . L , ., , . ~ , p . ~ , concentrated sulfuric acid was refluxed for 15 hours. After the reaction was complete, the solvent was distiIled away under reduced pressure to leave a residue, to which was added water.
The ~sulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation to . . ~ .
give an oily residue. Distillation of the residue under reduced pressure afforded 3.5 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester as a colorless oil. Mass spectrum :
parent ion 288 m/e.
19 ' .
: . . . . . .
~7~34 Example 8 To a solution of 2.2 g of 2-pyridinemethanol in 20 ml of tetrahydrofuran were added 3 g of 2-(4-isobutylphenyl)propionic acid chlorids and subsequently 2.7 g of triethylamine, and the mixture was reacted at room temperature for 2 hours. A~ter the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distilla-tion to leave a residue, to which was added water. The result-ing mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtalned was distllled in vacuo to give 3.5 g of 2-(4-iso-butylphenyl)propionic acid-2-pyrldylmethyl ester as a pale yellow oil, boiling at 138-140C/0.15mmHg. Mass spectrum : parent ion 297 m/e.
Example 9 To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.7 g of m-fluorobenzyl alcohol in 30 ml of : .
tetrahydrofuran was added 3.7 g of triethylamine,dropwise under cooling, and the mixture was reacted at room temperature for l.S hours. After the reaction was complete, the crystals procuced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with . .. .
ether. The ether extract was dehydrated and freed of ether by distillation, The oily residue thus obtained was tistilled in vacuo to yield 5.9 g of 2-(4-isobutylphenyl~propionic acid-m-fluorobenzyl ester as a colorless oil, boiling at 143-144C/0.2 mmHg. Mass spectrum : parent ion 314 m/e.
--. .. ,. . - .
' ' , . . .
, 1q~76134 Example 10 To a solution o 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.5 g of p-methylbenzyl alcohol in 30 ml of tetra-hydrofuran was added 3.7 g of trimethylamine,dropwise under cool-ing, and reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was dehydrated and freed of solvent by distillation to give an oily residue.
This residue was then distilled in vacuo to yield 6.3 g of 2-~4-isobutylphenyl)propionic acid-p-methylbenzyl ester as a .
colorless oil, boiling at 139-140C/O.lmmHg. Mass spectrum : -parent ion 310 m/e.
;; . " - .~
Example 11 A mixture o 5 g of 2-(4-isobutylphenyl)propionic acid, 7.3 g o n-propyl alcohol and 7,1 g of sulfuric acid was refluxed -~: :
~ or 6 hours. After coolingJ to the mixture was added ice-water.
.
- The resulting mixture was extracted with ether, and the extract was dehydrated. The ether was removed by distillation from the extract to leave an oily product, This product was distilled in vacuo to give 5.4 g o 2-(4-isobutylphenyl)propionic acid-.
n-propyl ester as a colorless oil, boiling at 100-103C/0.3mmH~.
Mass spectrum : parent ion 248 m/e.
: .
21 ~:
. . . .. . . .. .... .
.
2xample 12 1076134 To a solution of 3.5 g of p-isobutylphenylacetic acid sodi-um salt in 20 ml of dimethylformamide was added 5.9 g of o-chloro-benzyl chloride, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the mixture was cooled to produce an inorganic substance, which was then removed by filtration. The iltrate was freed of dimethylformamide by distillation in vacuo to give an oily product. Distillation of this product in vacuo yielded 3.8 g of p-isobutylphenyIacetic acid-2-chlorobenzyl ester as a colorless oil, boiling at 145-147 C/lmmHg. Analysis - Calculated for C~9H2lClO2 : C, 72.03 ;
, H, 6.68. Found : C, 71.98 ; H, 6.51. Mass spectrum :parent ion 316 m/e.
Example 13 To a solution of 3.5 g of p-isobutylphenylacetic acid chlo-ride in 5.9 g of 2-methoxyethanol was added 1.6 g of tri-ethylamine, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, an inorganic sub-stance produced was filtered off. The filtrate was extracted , with ether, and the extract was washed, dehydrated and applied over a column of silica gel. The adsorbates was eluted with ether, an~ the eluates were freed of ether to give an oily product. Distillation o the product in vacuo gave 2.8 g of p-isobutylphenylacetic acid-2-methoxyethyl ester as a colorless oil, boiling at 97-98C/lmmHg. Analysis - Calculated for ClsH22O3 : C, 71.97 ; H, 8.86. ~ound : C, 71.63 ; H, B.90.
Mass spectrum : parent ion 250 m/e.
07 6~ 3 4 ~xample 14 A mixture o~ 1.73 g of 4-isobutylphenylacetonitril~ and 10 g of 95 % 2,2,2-tri~luoroethanol ant 10 g of concentrated sulfuric ~-~
acid were refluxed for 12 hours. After the ~eaction was complete, ice-water was added to the mixture. The resulting mixture was -extracted with ether. Tha ethar layer separated was dehytrated and concentratet to leaYe an oily residue. The residue was distilled in vacuo to give 1.4 g of 4-isobutylphenylacetic acid -2,2,2-trifluoroothyl ester as a pale yellow oil, boiling at 77-79C/lmmHg. Analysis- Calculated or Cl4HI7F3O2 : C, 61.3G ;
H, 6.25. Found : C, 61.21 ; H, 6.23.
~xample 15 A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethyl-pyridine was hsated at 65-70C ~or 10 hours.~ To this mi~ture was added 2.1 g of p-isobutylphenylace~ic acid methyl ~ster,and the whole was heated at 9S-100C ~or 8 hours. A~t~r the reac-tlon~was complete, 100 ml of water was added. The resulting mix-ture was extracted with ether, and the ether layer separated was dehydrat~d and concentrated to lsave an oily residu~.
This residue was distilled undar roduced pressure to give 1.9 g of p-isobutylphenylacetic acid-3-pyridylmethyl aster as a colorless liquid, boiling at 142-145C/lmmHg. Analysis-Calcu-latad for CltH2~NO2 : C, 76.29 ; H, 7.47 ; N, 4.94. Found :
C, 76.02 ; H, 7.38 ; N, 4.79. Mass spoctrum : par~nt ion 283 m/e.
j 23 ~
. , , . :, . . ",,, - :
. . . ,, ., ,, . , . . . .; , . . .. . .
.: . . , , , , .: , , . ; :,,, ,., :
~ 1)76134 Example 16 A mixture of 1.9 g of p-isobutylphenylacetic acid, 10 ml of 2,2,2-trifluoroethanol and 1 ml of concentrated sulfuric acid was refluxed for 5 hours. After the reaction was complete, the mixture was poured into ice-water. The resulting mixture was neutralized with adding 5 % sodium carbonate solution, and then --extracted with ether. The ether layeT separated was dehydrated and concentrated to leave an oily residue. The residue was distilled in vacuo to yeild 2.3 g of p-isobutylphenylacetic acid-2,2,2-trifluoroethyl ester as a colorless liquid, boiling at 78-79C/lmmHg. Analysis-Calculated for Cl4HI7F3O2 :
;~ ~C, 61.30 ; H, 6.25. Found : C, 61.01 ; H, 6.15. Mass spectrum :
~ ~ parent ion 274 m/e.
' :~
~ ~ .
2~
~ ~ .
.. .. . ..
. . ., ._ . _ , ~
7 2 _ -CN ~ "(103-104/1.0) Z83 ~: 7 3 ,. -CH2 ~ . "(142-145/1.0) 283 _ _ _ _ _ ...
7 4 " -CH2 ~ "(106-108/1.0) 283 . . . .
7 5 " -CH2Gl ~ ~~150-153/1.0) 317 ; .
~ . _ ., ~ 7 6 -CH2 ~(73-75/0.15) 276 : '~
;
, : ~ . . . ~ . .. .
.. .
- - , ' , ' ' ' ,. -, ,, ', ' .,, ;' : ' , ~ , " ." "' . ,~ ' - , ~L07613q~
All of the compounds prepared by the process o the pre-sent invention were firs~ tested for their acute toxicities, and subsequently for their pharmacological ac~ivities such as anti-in~lammatory and analgetic activity. It is fount that certain of the compounds preparet by the process of the present inven-tion have shown a high degree of pharmacological activities with low toxicity. Especially, topical application of the said com-pounds h~s produced a higher anti-inflammatory potency than that of ibuprofen. The testing methods are described in the following, and the results are summarized in Table ~ .
(1) Acute toxicity Each test compound suspended in O.S % tragacanth-saline was administered intraperitoneally or orally to male mice of dd-strain(body weight 16-24 g). The lethal dose was estimated from the death of animals 72 hours following administration.
~2) Anti-inflammatory activity for oral route A group of five male rats of Wistar-strain(body weight 100-150 g ) were orally given each test compound suspended in O.S % tragacanth-saline. After 30 minutes 0.5-1.0 % carrageenin suspended in the water for injection was injected subcutaneously to a hind paw. After 3 hours the carrageenin adema was measured by volume, and the percent inhibition was determined with respect to the results for the control animals. Por comparison, the percent inhibition o~ each test compound prepared by the process of the present invention was divided by that of the reerence compound, ibuproen t2-(p-isobutylphenyl)propionic acid],to give the relative inhibition, which is included in Table ~ . The mean percent inhibition o~ ibuprofen was 37.4 % at a dose of 50 mg/kg .... ., : . ,, ,, , ., ,, . ,- . . .... . . .. .. .. .. . .
and 33.5 % at lO mglkg.
(3) Anti-inflamma~ory activity for ~opical rou~e The dorsal skin ef male rats of Wistar-straintb~dy weight :
about 100 g) were depilated. Carrageenin suspension was injected intra-dermally at a dose of 250~/0.05ml/site. The filter paper (size : 2.3 cm in diameter) was impregnated with 1 % test com-pound dissolved in polyethylene glycol 300. Immediately after injection, the filter paper containing 125.2 + 18.0 mg of the polyethylene glycol was applied on the injected site. After 3 hours, 1 % pontamine sky blue solution was injected intrave-nously at a dosc of 0.5 ml/kg. After further 3 hours, the animals were sacrificed and their dorsal skin were removed to measure the area of leakage of the pigment. The percent inhibition was determined with respect to the resul~s for the control animals.
Fo~ comparison, the percent inhibition of each test compound prepared by the process of the present invention was dlvided by ~that of the reference compound, ibuprofen, to giva the relative inhibition. The mean percent inhibition of ibuprofen was 23,8 ~.
(4) Analgetic activity Each test compound suspended in 0.5 % tragacanth-saline was orally administered to dd-strain micetbody weight : 18-20 g ).
After one hour 0.6 % acetic acid solution was injected intra-peritoncally in a volume of O.lml/10 g. The writhing syndrome was observed for 10 minutes from 30 minutes after injection, and S0 % analgetic ef~ective dose(~Ds0) and its 95 % confidence limit were calculated by Litchfield-Wilcoxon's method.
; . . ..
~(97~;13~
Table ~
Pharmacological Ef~cts and Acute Toxici~y o~ tha Object Com-pound, Ph~nylace~ic Acid Derivatives obtained by the Present Inve~ion :
_. . . _ . _ anti-in1ammator I analgetic acute ~ffect effect toxicity Standard compound oral topica~ EDso (mg/kg) 50 10 ~mg/kg) g/kg mg/kg (95%C.L.) oral . ~ _ ibupro~en l 1.0 1.0 1.0 45 8 1000-2000 .
_ _ _ _ Object Compound of anti-infLammator I analgetic acute General Formula [A] effect effect toxicity R' H3C\ fi-~ I BDso (mg/kg) :~ CHCH2~Y ~CHCOOR
H3C/ ~ ~mg/kg) oral ~A] oral topical ~ . ~
:~ R R 50 10 (95%C.L.) m~/k~ mg/kg _ _ .
::~ CH3 -CH~ 1.4 0.8 3.5:(107.3 111.1)~2000 _ ~ ~-CH2CH2CH 3 1.1 0.7 3.2 192 3 ~2000 :;: . . . . ~ __ ~ : -~CH2~sCH3 1.2 ~ 13, 5(197,9 231.9) >2000 . _ : _ -CH2CP3 1.3 0.8 3.6(I29.4 139.8)1000-2000 : .- -CH2CH2OH 1.0 0.S 1.9(148.8-161.0)~2000 _ ~ _ , _ , '.
-CH28HCH2OH 0,9 1.1 142.9 1000-2000 . _ , _. .':: ' .. -CH2OCH3 1.2 1.0 2.5(145.1 203.3)500-1000 ~ _.
-CH2OC2Hs 1.0 1.3 2.8(151.8-158.0)~2000 __ _ ~ .
L_____ -CH2CH20CH3 1.20.4 1.2 405.51000-2000 :.
13 :
,: : : :....... . ,: , , :, ,`,. , . , . : ~ .. . ..
.. . . . .. ... . . . . . . . . . .
... . . . . . .. . .. .. . . . ...
. : :, . . , . . , , " . .. . . .. . .
1~)76~34 I .
anti-inflammatory ¦ analgetic acute . .
. effect effect toxicity R Roral ¦topical EDs o (mg/kg) 50 10 1 (mg/kg) mg/kg mg/kg (95 % C . L . ) ora 1 CH3 -CH2CH20C2Hs 0.9 O. 7 1.2 (130 0 181 2) 1>2000 . l .. -CH2CH20C:H2CH20H 0.9 2.3 (143.3 158 7~ ¦>2000 : i -I
~ -CH20COCH3 0.9 0.9 _ _ " : -CH2CH20COCH3 1.1 0.7 2.2(285.9-329.3) >2000 _ _ _ 1. -~CH2COOC2Hs O.7 O. 5 1.9~ 146 3 - 214.3) > 2000 . , .
~ -CH2 ~ 1 1. 6 O .8 3.7( 98.6 108.0) 2000 _ . .
: -CH2 ~ O.9 O. 7 3.1(114.3 - 122.3) ~ 2000 ~ ~ Cl~ 1.0 0. S2. S( 3 7.1 65. 7 ) > 2000 :: :
:~ : ~ ,. -CH2- ~ Cl 1.O :O. 52.8 486 4 >2000 -- -CH2 ~ 1.7 1.6 ~( 183.2 220.6) '~5 ~ : -CH2 ~ 1.7 0.8 0.9(619.7 - 648.1) 1~ . ..
~:~ : ll -CH2 ~ F 1.2 1.1 ~; -- -CH2 ~ CH3 1.5 1.7 1.9¦(190.1- 269.2) --I - CH2 ~OCH 3 1.4 0.8 I Z .3¦ (203.2 - 236.4) L ~ -CH ~ ~ 1.O 0.6 L~ ( 70.9 88.3 ) i~
~ -CH2CH2N/cH3 ¦ 1.2 L~ Z, o 53 7 1000-2000 , . .
:-:, .. .. .. ,. - : . ,. . :
- ~ . .. . . . . - :: , . .. . , ~ .. ~. . . .
- . . .. ... .. . .. . .
... , .-: ,, ,, . : . . . . . .. . . .
.. . , , . . . :
.. ~ . . . . .. .
1(~7~134 _ . . . .
anti-inflammatory analgetic acut~
. effect effect toxicity , R R oral topical ED 5 D (mg/kg) 50 10 (mg/kg) . mg/kg mg/kg (95tC.L.) oral _ _ CH3 -CH2CH2N'C2H5 0.9 1.2 3.0 317.7 500-1000 _ ~ ll -CH2CH2GH2N~CcH3 1.1 0.7 2.2 ( 24.7 35.1 ) S00-1000 :
. - ........ . _ " -CH2CHi-N O 0.9 0.7 1.6 tl49.3 159.l) 1000-2000 "; -CU2CH2-N N-CH ¦ 1.1 1.0 2.5 ~ 19.8 43.4 ) 1000-2000 ~ _.. . . . .,. ., .. . . . . - --................... = _ : -CH2 ~ 1.8 0.7 4.0 ( 32.5 103.1) 1000-2000 :~ ~ ll -CH2 ~ 1.4 1.0 1.7 ( 26.2 36.2 ) 1000-2000 :: : l _ : ~ " -CH2 ~ 1.2 1.0 2.7 87.1 >2000 . . _ _ l " -CH2 ~ 2.5 0.8 1.8 762.0 >2000 Cl _ ;: _ -CHI ~ 0.9 0.6 3.1 ( 56.0 127.2) 1 1000-2000 : ". '"
~ , :
,~
~:
: ~ .' ,' ~
':'. .
, .. , . .... ... , .. , ... .. . , , . . ~ , . .. . . . . ...
... . .. . . . . .. . .
- :-, ., ; , . :. . , , . , : .
:. .,: . . . . .. . . , , , , ~, . . . . . .
~761~
Some of the preferred embodiments of the present invention are disclosed in the following examples. ~ -Example A mixture of 3.3 g of 2-(p-isobutylphenyl) propicnic acid sodium salt, 2.3 g of dimethylaminoethyl chloride and 30 ml of ~
benzene was refluxed for 12 hours. A solid mass produced was `~-filtered of, and the benzene was distilled away from the filtrate ~- -under reduced pressure to leave an oily residue. This residue was distilled under reduced pressure to give 3.5 g of 2-(p-isobutyl-phenyll propionic acid dimethylaminoethyl ester as a colorless oil, .
boiling at 133-136c/lmmHg. Analysis-calculated for C17H27N02 C, 73.6I~; H, 9.81; N, 5.05. Found: C, 73.50; H, 9.72;
N, S.02O The infrared spectrum showed strong C=0 absorportion at 1730 cm 1 characteristic for ester Mass spectrum: parent ion 277 m/e.
Example 2 ..
.
~ ~ A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethyl-.,. .
~ ~pyridine was heated at 65-70C for 10 hours. To this mixture `
".
was added 3.8 g of 2-(p-isobutylphenyl) propionic acid methyl euter, and the whole was heated at 95-100C for 8 hours. After cooling to room tempe~ature, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether was distilled away from the extract to leave a re~idue. The residue was passed through a column of sîlica gel, and the adsorbate was eluted with chloroform. The eluates were freed of chloro-form in vacuo to give 2.9 g of 2-(p-isobutylphenyl) propionic acid-3-pyridylmethyl ester as a colorless oil. The infrared spectrurn showed strong C=0 absorption at 1730 cm~l characteri~tic for ester. Mas~ spectrum: parent ion 297 m~e.
, , ~ ,, .
107613~
Example 3 To a mixture of 2.28 g of 2-(p-isobutylphenyl)propionic acid sodium salt in 20 ml of dimethylformamide was added 2.52 g of benzyl chloride and the whole was heated at 90 C for 3 hours.
After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether and the extract was dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.57 g of 2-(p-isobutyl-phenyl)propionic acid benzyl ester as a colorless oilj boiling .
at 108-110C/O.lmmHg. Analysis- Calculated for C20H2402 :
C,~ 81.04 ; H, 8.16. Found : C, 80.92 ; H, 8.02.
Example 4 ;; To a mixture of 2.24 g of 2-(p-isobutylphenyl)propionic acid chloride and 2.10 g of p-methoxybenzyl alcohol in 20 ml ;;
` ~of~tetrahydrofuran was added 1.50 g of triethylamine under :
cooling and the whole was stirred or 2 hours. Ater the reaction was complete, an insoluble matter produced was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue thus obtained was added water and the resulting mixture was extracted with ether. The ether layer separated was washed with succes-sive, 5 % sodium carbonate solution, 5 % hydrochloric acid solution and water, and then dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.81 g of 2-(p~isobutyl-,~
... . .. . . ..
.. .. .
. .
~` 10~6i34 phenyl)propionic acid-p-methoxybenzyl ester as a colorless oil, boiling a~ 149-151C/O.lmmHg. Analysis- Calculated for C2lH2603 : C, 77.27 ; H, 8.03. Found : C, 77.11 ; H, 8.12.
Example 5 A mixture of 4.12 g of 2-(p-isobutylphenyl)propionic acid, lS ml of 2,2,2-trifluoroethyl alcohol and 4.9 g of concentrated sulfuric acid was heated at 100 C for 12 hours. After the reaction was complete, the mixture was poured into ice-water and the resulting mlxture was extracted with ether. The ether layer separated was washed sufficiently with successive S ~
sodium carbonate solution and water, and dehydrated. The ether was removed by distillation to give an oily product. Distilla-tion of the product in vacuo yielded 4.95 g of 2^(p-isobutyl-phenyl)propionic acid-2,2,2-trifluoroethyl es*er as a pale yellow oil, boiling at 73-74C/0.12mmHg. Analysis- Calculated for ClsHlgF302 : C, 62.48 ; H, 6.64. Found : C, 62.31 ; H, 6.61.
Example 6 A mixture of 0.05 g of sodium in 20 ml of cyclopropylmethyl alcohol was heated at 50 C for S hours. To the mixture was added 2.2 g of 2-(p-isobutylphenyl)propionic acid methyl ester and the whole was refluxed for 10 hours. After the reaction - was completed, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water.
The resulting mix~ure was extracted with ether, and the extract was washed sufficiently with water and then dehydrated. The ether;was removed by distillation to leave a residual oily product.
' .
.. . . .
, , . ' ~ :
., , ... ~ .
, 11)76134 , This product was then distilled under reduced pressure to yield 1.38 g of 2-~p-isobutylphenyl)propionic acid cyclopropyl-methyl ester as a colorless oil, boiling at lO9-111C/lmmHg.
Analysis - Calculated for C~?H~402 : C, 78.42 ; H, 9.29.
Found : C, 78.19 ; H, 9.22.
Example 7 A mixture of 3.0 g of 2-(p-isobutylphenyl)propionic acid anhydride, 3.8 g of 2,2,2-trifluoroethyl alcohol and 0.5 cc of ;-~a ~ . L , ., , . ~ , p . ~ , concentrated sulfuric acid was refluxed for 15 hours. After the reaction was complete, the solvent was distiIled away under reduced pressure to leave a residue, to which was added water.
The ~sulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation to . . ~ .
give an oily residue. Distillation of the residue under reduced pressure afforded 3.5 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester as a colorless oil. Mass spectrum :
parent ion 288 m/e.
19 ' .
: . . . . . .
~7~34 Example 8 To a solution of 2.2 g of 2-pyridinemethanol in 20 ml of tetrahydrofuran were added 3 g of 2-(4-isobutylphenyl)propionic acid chlorids and subsequently 2.7 g of triethylamine, and the mixture was reacted at room temperature for 2 hours. A~ter the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distilla-tion to leave a residue, to which was added water. The result-ing mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtalned was distllled in vacuo to give 3.5 g of 2-(4-iso-butylphenyl)propionic acid-2-pyrldylmethyl ester as a pale yellow oil, boiling at 138-140C/0.15mmHg. Mass spectrum : parent ion 297 m/e.
Example 9 To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.7 g of m-fluorobenzyl alcohol in 30 ml of : .
tetrahydrofuran was added 3.7 g of triethylamine,dropwise under cooling, and the mixture was reacted at room temperature for l.S hours. After the reaction was complete, the crystals procuced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with . .. .
ether. The ether extract was dehydrated and freed of ether by distillation, The oily residue thus obtained was tistilled in vacuo to yield 5.9 g of 2-(4-isobutylphenyl~propionic acid-m-fluorobenzyl ester as a colorless oil, boiling at 143-144C/0.2 mmHg. Mass spectrum : parent ion 314 m/e.
--. .. ,. . - .
' ' , . . .
, 1q~76134 Example 10 To a solution o 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.5 g of p-methylbenzyl alcohol in 30 ml of tetra-hydrofuran was added 3.7 g of trimethylamine,dropwise under cool-ing, and reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was dehydrated and freed of solvent by distillation to give an oily residue.
This residue was then distilled in vacuo to yield 6.3 g of 2-~4-isobutylphenyl)propionic acid-p-methylbenzyl ester as a .
colorless oil, boiling at 139-140C/O.lmmHg. Mass spectrum : -parent ion 310 m/e.
;; . " - .~
Example 11 A mixture o 5 g of 2-(4-isobutylphenyl)propionic acid, 7.3 g o n-propyl alcohol and 7,1 g of sulfuric acid was refluxed -~: :
~ or 6 hours. After coolingJ to the mixture was added ice-water.
.
- The resulting mixture was extracted with ether, and the extract was dehydrated. The ether was removed by distillation from the extract to leave an oily product, This product was distilled in vacuo to give 5.4 g o 2-(4-isobutylphenyl)propionic acid-.
n-propyl ester as a colorless oil, boiling at 100-103C/0.3mmH~.
Mass spectrum : parent ion 248 m/e.
: .
21 ~:
. . . .. . . .. .... .
.
2xample 12 1076134 To a solution of 3.5 g of p-isobutylphenylacetic acid sodi-um salt in 20 ml of dimethylformamide was added 5.9 g of o-chloro-benzyl chloride, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the mixture was cooled to produce an inorganic substance, which was then removed by filtration. The iltrate was freed of dimethylformamide by distillation in vacuo to give an oily product. Distillation of this product in vacuo yielded 3.8 g of p-isobutylphenyIacetic acid-2-chlorobenzyl ester as a colorless oil, boiling at 145-147 C/lmmHg. Analysis - Calculated for C~9H2lClO2 : C, 72.03 ;
, H, 6.68. Found : C, 71.98 ; H, 6.51. Mass spectrum :parent ion 316 m/e.
Example 13 To a solution of 3.5 g of p-isobutylphenylacetic acid chlo-ride in 5.9 g of 2-methoxyethanol was added 1.6 g of tri-ethylamine, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, an inorganic sub-stance produced was filtered off. The filtrate was extracted , with ether, and the extract was washed, dehydrated and applied over a column of silica gel. The adsorbates was eluted with ether, an~ the eluates were freed of ether to give an oily product. Distillation o the product in vacuo gave 2.8 g of p-isobutylphenylacetic acid-2-methoxyethyl ester as a colorless oil, boiling at 97-98C/lmmHg. Analysis - Calculated for ClsH22O3 : C, 71.97 ; H, 8.86. ~ound : C, 71.63 ; H, B.90.
Mass spectrum : parent ion 250 m/e.
07 6~ 3 4 ~xample 14 A mixture o~ 1.73 g of 4-isobutylphenylacetonitril~ and 10 g of 95 % 2,2,2-tri~luoroethanol ant 10 g of concentrated sulfuric ~-~
acid were refluxed for 12 hours. After the ~eaction was complete, ice-water was added to the mixture. The resulting mixture was -extracted with ether. Tha ethar layer separated was dehytrated and concentratet to leaYe an oily residue. The residue was distilled in vacuo to give 1.4 g of 4-isobutylphenylacetic acid -2,2,2-trifluoroothyl ester as a pale yellow oil, boiling at 77-79C/lmmHg. Analysis- Calculated or Cl4HI7F3O2 : C, 61.3G ;
H, 6.25. Found : C, 61.21 ; H, 6.23.
~xample 15 A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethyl-pyridine was hsated at 65-70C ~or 10 hours.~ To this mi~ture was added 2.1 g of p-isobutylphenylace~ic acid methyl ~ster,and the whole was heated at 9S-100C ~or 8 hours. A~t~r the reac-tlon~was complete, 100 ml of water was added. The resulting mix-ture was extracted with ether, and the ether layer separated was dehydrat~d and concentrated to lsave an oily residu~.
This residue was distilled undar roduced pressure to give 1.9 g of p-isobutylphenylacetic acid-3-pyridylmethyl aster as a colorless liquid, boiling at 142-145C/lmmHg. Analysis-Calcu-latad for CltH2~NO2 : C, 76.29 ; H, 7.47 ; N, 4.94. Found :
C, 76.02 ; H, 7.38 ; N, 4.79. Mass spoctrum : par~nt ion 283 m/e.
j 23 ~
. , , . :, . . ",,, - :
. . . ,, ., ,, . , . . . .; , . . .. . .
.: . . , , , , .: , , . ; :,,, ,., :
~ 1)76134 Example 16 A mixture of 1.9 g of p-isobutylphenylacetic acid, 10 ml of 2,2,2-trifluoroethanol and 1 ml of concentrated sulfuric acid was refluxed for 5 hours. After the reaction was complete, the mixture was poured into ice-water. The resulting mixture was neutralized with adding 5 % sodium carbonate solution, and then --extracted with ether. The ether layeT separated was dehydrated and concentrated to leave an oily residue. The residue was distilled in vacuo to yeild 2.3 g of p-isobutylphenylacetic acid-2,2,2-trifluoroethyl ester as a colorless liquid, boiling at 78-79C/lmmHg. Analysis-Calculated for Cl4HI7F3O2 :
;~ ~C, 61.30 ; H, 6.25. Found : C, 61.01 ; H, 6.15. Mass spectrum :
~ ~ parent ion 274 m/e.
' :~
~ ~ .
2~
~ ~ .
.. .. . ..
Claims
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS :
1. The process for preparing phenylacetic acid derivatives of the following general formula :
[wherein R is selected from the group consisting of lower alkyl(other than ethyl) and substituted lower alkyl ; R' is selected from the group consisting of hydrogen and methyl], which comprises reacting a compound of the following general formula :
[wherein R' has the same meanings as defined above ; X is selected from the group consisting of carboxyl, carbonic acid metal salt, haloformyl, lower alkoxycarbonyl, cyano and acid anhydride residue()] with a compound of the following general formula :
RY
(wherein R has the same meanings as defined above ; Y is selected from the group consisting of hydroxyl, halogen and organic sulfo-nyloxy).
[wherein R is selected from the group consisting of lower alkyl(other than ethyl) and substituted lower alkyl ; R' is selected from the group consisting of hydrogen and methyl], which comprises reacting a compound of the following general formula :
[wherein R' has the same meanings as defined above ; X is selected from the group consisting of carboxyl, carbonic acid metal salt, haloformyl, lower alkoxycarbonyl, cyano and acid anhydride residue()] with a compound of the following general formula :
RY
(wherein R has the same meanings as defined above ; Y is selected from the group consisting of hydroxyl, halogen and organic sulfo-nyloxy).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50156799A JPS5826744B2 (en) | 1975-12-24 | 1975-12-24 | Shinkinapropionsan Ester Yudou Tino Seizou |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076134A true CA1076134A (en) | 1980-04-22 |
Family
ID=15635562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA267,690A Expired CA1076134A (en) | 1975-12-24 | 1976-12-13 | Process for preparing phenylacetic acid ester derivatives |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5826744B2 (en) |
| AU (1) | AU507661B2 (en) |
| CA (1) | CA1076134A (en) |
| CH (1) | CH617919A5 (en) |
| DE (1) | DE2658610C2 (en) |
| FR (1) | FR2336126A1 (en) |
| GB (1) | GB1573322A (en) |
| NL (1) | NL180381C (en) |
| SE (1) | SE433492B (en) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54144336A (en) * | 1978-07-24 | 1979-11-10 | Teikoku Seiyaku Kk | Propionic acid propylester derivative*its manufacture and antiiinflammatory and sedative agent containing it |
| JPS5517358A (en) * | 1978-07-24 | 1980-02-06 | Teikoku Seiyaku Kk | Butyl propionate derivative, its preparation, and antiphlogistic and analgesic comprising it |
| JPS5587770A (en) * | 1978-12-27 | 1980-07-02 | Hisamitsu Pharmaceut Co Inc | Preparation of 2-(p-isobutylphenyl)propionic acid 2-pyridinemethyl ester |
| JPS57203035A (en) * | 1981-06-05 | 1982-12-13 | Taisho Pharmaceut Co Ltd | Carboxylic acid ester |
| DE3225290A1 (en) * | 1982-07-07 | 1984-01-12 | Merck Patent Gmbh | RING CONNECTIONS |
| YU43408B (en) * | 1985-04-26 | 1989-06-30 | Lek Tovarna Farmacevtskih | Process for preparation of 2-(4-isobuthylphenyl)-prophiohydroxamic acid |
| JPH0635378B2 (en) * | 1985-06-27 | 1994-05-11 | ポ−ラ化成工業株式会社 | Cosmetics |
| ES2004447A6 (en) * | 1987-07-06 | 1989-01-01 | Sune Coma Nuria | New 2-(P-isobutylphenyl)-propionic acid ester and process for the preparation thereof. |
| DE3811118C1 (en) * | 1988-03-31 | 1989-10-12 | Merckle Gmbh, 7902 Blaubeuren, De | |
| IT1217589B (en) * | 1988-05-13 | 1990-03-30 | Pulitzer Italiana | ANTI-INFLAMMATORY AGENT FOR THERAPY OF PROSTATIC HYPERTROPHY, ITS PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
| JPH0639449B2 (en) * | 1989-04-10 | 1994-05-25 | エーザイ株式会社 | Polyprenyl compound, method for producing the same, and medicament containing the same |
| ES2148175T3 (en) | 1991-05-13 | 2000-10-16 | Boots Co Plc | PHARMACEUTICAL COMPOSITION CONTAINING A SALT OF IBUPROFEN. |
| US6399618B1 (en) | 1997-07-09 | 2002-06-04 | Cardiome Pharma Corp | Compositions and methods for modulating sexual activity |
| CN103948571A (en) * | 2006-07-18 | 2014-07-30 | 天津昕晨泰飞尔医药科技有限公司 | Water-soluble ibuprofen prodrug with high skin penetration rate and positive charge |
| JP5424880B2 (en) * | 2006-08-15 | 2014-02-26 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
| KR20150058566A (en) | 2007-06-04 | 2015-05-28 | 테크필즈 인크 | Pro-drugs of NSAIAs With Very High Skin and Membranes Penetration Rates and Their New Medicinal Uses |
| WO2013064153A1 (en) * | 2011-10-31 | 2013-05-10 | Claus Selch Larsen | Prodrugs of non- steroid anti - inflammatory agents (nsaids) |
| US9759472B2 (en) | 2012-12-13 | 2017-09-12 | Whirlpool Corporation | Clear ice maker with warm air flow |
| US9500398B2 (en) | 2012-12-13 | 2016-11-22 | Whirlpool Corporation | Twist harvest ice geometry |
| US9470448B2 (en) | 2012-12-13 | 2016-10-18 | Whirlpool Corporation | Apparatus to warm plastic side of mold |
| US9557087B2 (en) | 2012-12-13 | 2017-01-31 | Whirlpool Corporation | Clear ice making apparatus having an oscillation frequency and angle |
| CN105461731B (en) * | 2014-08-07 | 2017-05-24 | 富力 | Phillygenin ibuprofen ester, preparation and applications thereof |
| US9915458B2 (en) | 2014-10-23 | 2018-03-13 | Whirlpool Corporation | Method and apparatus for increasing rate of ice production in an automatic ice maker |
| JP6153264B2 (en) * | 2015-01-05 | 2017-06-28 | テックフィールズ インコーポレイテッド | NSAIA prodrug with very fast skin and membrane permeation rate and novel pharmaceutical use thereof |
| CN109134261A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| CN109134262A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| US10907874B2 (en) | 2018-10-22 | 2021-02-02 | Whirlpool Corporation | Ice maker downspout |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
-
1975
- 1975-12-24 JP JP50156799A patent/JPS5826744B2/en not_active Expired
-
1976
- 1976-12-06 SE SE7613651A patent/SE433492B/en not_active IP Right Cessation
- 1976-12-13 CA CA267,690A patent/CA1076134A/en not_active Expired
- 1976-12-21 FR FR7638482A patent/FR2336126A1/en active Granted
- 1976-12-21 CH CH1607276A patent/CH617919A5/en not_active IP Right Cessation
- 1976-12-23 DE DE2658610A patent/DE2658610C2/en not_active Expired
- 1976-12-23 AU AU20878/76A patent/AU507661B2/en not_active Expired
- 1976-12-23 NL NLAANVRAGE7614308,A patent/NL180381C/en not_active IP Right Cessation
- 1976-12-24 GB GB51350/76A patent/GB1573322A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2336126A1 (en) | 1977-07-22 |
| GB1573322A (en) | 1980-08-20 |
| AU507661B2 (en) | 1980-02-21 |
| SE7613651L (en) | 1977-06-25 |
| AU2087876A (en) | 1978-06-29 |
| FR2336126B1 (en) | 1979-03-09 |
| JPS5826744B2 (en) | 1983-06-04 |
| NL180381C (en) | 1987-02-16 |
| JPS5278848A (en) | 1977-07-02 |
| NL180381B (en) | 1986-09-16 |
| CH617919A5 (en) | 1980-06-30 |
| SE433492B (en) | 1984-05-28 |
| NL7614308A (en) | 1977-06-28 |
| DE2658610A1 (en) | 1977-07-07 |
| DE2658610C2 (en) | 1982-12-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1076134A (en) | Process for preparing phenylacetic acid ester derivatives | |
| FI87454B (en) | POLYCYCLISKA AROMATISKA DERIVAT, DERAS FRAMSTAELLNINGSFOERFARANDE OCH TILLAEMPNING INOM KOSMETIK. | |
| CA1153384A (en) | 6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives | |
| DD143909A5 (en) | PROCESS FOR THE PREPARATION OF 4-SUBSTITUTED PHENOXY DERIVATIVES | |
| US3933838A (en) | 5-Substituted 2-amino-4-arylthiazoles | |
| US4150137A (en) | Pyridylalkyl esters of 2-(p-isobutylphenyl)acetic acid and propionic acids and use | |
| US3956374A (en) | Aryl-oxo-heptenoic acids | |
| EP0116360B1 (en) | 1-phenyl-2-aminocarbonyl indoles, their preparation and medicines containing them | |
| CH633250A5 (en) | METHOD FOR PRODUCING NEW POLYPRENYL DERIVATIVES. | |
| US3957794A (en) | 3-Amino-2,3,3a,6,7,7a-hexahydro-thieno[3,2-b]pyridin-(4H)5-one | |
| US4165428A (en) | Indoleacetic acid ester derivatives | |
| DE2929760C2 (en) | ||
| US4154734A (en) | Amides of 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylic acid-7,7-dioxide | |
| US4322428A (en) | 2(4-Fluorophenyl)-4,5,-bis(4-methoxyphenyl)thiazole and method of use | |
| US3989738A (en) | Method of preparing phenolic antioxidants by condensing active methylene compounds with 3,5-di-tert alkyl-4-hydroxybenzylpyridinium salts | |
| Kato et al. | Studies on keten and its derivatives. Part 89. Ethyl 4-substituted acetoacetates: synthesis and reaction with diketen | |
| US3963758A (en) | 2-(Benzofuroyl)phenyl acetic acids | |
| Mase et al. | Imidazo [2, 1-b] benzothiazoles 3: syntheses and immunosuppressive activities of 2-(m-acyloxyphenyl) imidazo [2, 1-b] benzothiazoles | |
| US4335251A (en) | Phenyl-i-propionic acid esters and pharmaceutical use thereof | |
| US4009172A (en) | 2,3,3A,6,7,7A-Hexahydro-thieno[3,2-b]pyridin-(4H)5-ones | |
| SU584760A3 (en) | Method of preparing oxybiphenyl derivatives or salts thereof | |
| US4465855A (en) | Process for the preparation of arylacetic acid derivatives | |
| US3966741A (en) | Process for the preparation of substituted or unsubstituted 4-pyridylthioacetic acid | |
| CA1060903A (en) | Pharmaceutically useful indanylpropionic acid derivatives | |
| US4385004A (en) | Esters of ortho-allylphenol useful for the preparation of arylacetic acid derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |