CA1076139A - Method of producing indan derivatives - Google Patents
Method of producing indan derivativesInfo
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- CA1076139A CA1076139A CA268,042A CA268042A CA1076139A CA 1076139 A CA1076139 A CA 1076139A CA 268042 A CA268042 A CA 268042A CA 1076139 A CA1076139 A CA 1076139A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/16—Unsaturated compounds
- C07C61/39—Unsaturated compounds containing six-membered aromatic rings
Abstract
SUBSTITUTE
REMPLACEMENT
SECTION is not Present Cette Section est Absente
REMPLACEMENT
SECTION is not Present Cette Section est Absente
Description
7~39 ~(ethod of producing indan derivatives This invention relates to a novel method of producing indan derivatives of the general formula: ';
~. Rl R ~ (I) wherein Rl represents a hydrogen atom, an arylcarbonyl group or an arylcarbonyl group substituted by alkyl ha~ing 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen; R2 is a hydrogen atom ~ or a cycloalkyl group; and R3 is a hydrogen atom or a halogen atom.
i The indan derivatives of general formula ~I) have eminent ¦ 10 analgesic, antiinfla~matory and antipyretic properties and are of value as, for example, analgesics, antiinflammatory agents, antipyretics and other agents in huoan or animal use. For the production of these compounds, there are known the processes disclosed in United States Patent 3,923,866 and United States Patent 3,953,500, for instance.
Hovever, such known processes are not altogether satisfactory in such aspects as production steps, yield purification procedure ` ', and so forth.
The present invention seeks to provide a novel method for producing the indan derivatives of the general formula (I~ which has advantsges from the industrial point of view.
Tho present invention therefore relates to a method for producing an indan derivative of general formula ~I), which comprises tl~ reacting z compound of general formula:
Rl R
<~
,,, '' ' '' i c; ~ 107~
~ , wherein Rl, R2 and 23 have the meanings given above, with a sulfonylmethyl-isonitrile compound of the general formula:
wherein R4 represents an alkyl group of 1 to 4 carbon atoms; an aryl group which i; unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, or an aralkyl group or an aralkyl which is substituted by alkyl of I to 4 carbon atoms; in the presence of a baso to produce a methylideneindan compound of the general formula:
~3/ ~ ~IV~
! lo wherein Rl, R2, R3 and R4 have the meanings given above, and then ¦ (2) hydrolyzing the once-recovered methylideneindan compound. , Referring to thc above general formulas, the aryl moiety ¦ of said arylcarbonyl group Rl may for example be phenyl or naphthyl.
¦ This aryl group ~ se ~ay also be substituted, the substituents ¦ including straight-chain or branchcd lower alkyl groups having 1 j to 4 carbon atoms te.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, ~, isobutyl, t-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms ~e.g. methoxy, eth^xy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, etc.), or ha.ogen ~e.g. fluorine, chlorine, bromine, etc.). One or more of such substituents, which may be the same or different groups, may occur in optional positions on v ~ I
.. , ~_ . --. .. . .
I
;h ~ ~,076139 ~. ,.
the aryl group. In the general formulas, the cycloalkyl group R2 is one containing 5 to 7 carbon atoms ~e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) As examples of said halogen atom represented by R3, there may be mentioned chlorine, bromine, fluorine and iodine. As examples of aryl group represented by R4, there may be mentioned phenyl and naphthyl. The aralkyl group represented by R4 may for example be benzyl, phenethyl or the like. The aryl and aralkyl groups may have substituents in optional positions on the respective aromatic rings, said substituents boing j 10 alkyl groups of 1 to 4 carbon atoms, namely methyl, ethyl, propyl or butyl. The alkyl group, also alternatively designated by R4, is an alkyl group containing 1 to 4 carbon atoms, thus being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl.
In the method according to the present invention, a compound of gcneral formula tll) is first reacted with a sulfonyl-methylisonitrile coopound tIII) in the presence of a base.
As examples of the base, there may be mentioned metol alkoxides te.g. alkali metal alkoxide prepared from lower alcohols such as methanol, ethanol, t-butanol, etc. and alkali metals such as 1 20 sodium, potassium and the liXe), alkali metal hydrides te.g. sodium hydride, lithium hydride, etc.) and so on. When metal alkoxide is used, it is normally nore expedient to use it as a solution in the corresponding alco~ol.
This reaction is preferably carried out in a solvent, which may for example be an ether (e.g. dimethoxyethane, diethoxy- r ethane, :etrahydrofuran, dioxane or the liXe~, nitrile (e.g. acetonitrile, propionitrile or the like), alkyl halide Ce.g. methylene chloride, ~ ~ 1076139 `~. ethylene chloride, methylene bromide or the like2 and so on.
Thi5 reaction is usually carried out at a temperature ranging from -70 to 10C, preferably at a temperature between ~ -S0~ and 0C and mcre preferably at a temperature betwcen ~ -20 and 0C, although the n,ost preferable temperature varies with the type of solvent and of base employed and other conditions.
The aforesaid base is preferably used in a proportion of 1 to 1.5 moles per mole of compound (II), while said sulfonylmethylisonitrile f ~:~
:~"' .. - ,' ' I ' i " ~ .
"'~''''' . I "
,' ~ ~i ~
, i ~.
, : ' .,-~,., ... ,~,.......... ~ , .. ~ '' - 10761~3$
. .
compound (III) is preferably employed in an equimolar proportion relative to the base ~he resultant compound (IV) can be easily separated and purified by conventional separatory procedure~ such as extraction, recrystullization and so forth. While compound (IV) is normally o~tained as a mixture of two stereoisomers, it is generally a enable to crystallization and, as such a mixture, can be easily purified However, for the purpose of obtaining a compound (I), the compound (IV) need not necessarily be purified but the crude product once recovered may be direct]y sub-Jected to the next reaction ~or example, the residue which is obtained by the conce~tration of the reaction mixture can be employed to the next reaction. ~ 1 Then, the compound of general formula (IV) is hydro- , lyzed. The catalyst for hydrolysis may be whichever of an acid catalyst and a basic catalyst. As examples of the acid catalyst, there may be mentioned mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phos-phoric acid, etc., while said basic catalyst may for example be selected from among alkali metal hydroxides such as sodium h~droxide, potassium hydroxide and so forth.
While water alone may prove to be a useful solvent, the reaction time may be considerably reduced by the concurrent use of one of water-miscible ethers (e.g dioxane, tetra-hydrofurar., dimethoxyethane, diethoxyethane, etc ), w&~er- ~ !
miscible alcohols (e.g. methanol, ethanol, t-butanol, etc.) and water-miscible organic acids (e.g. acetic acid, propionic acid, e~^ ) It is particularly advantageous, for commercial . . , j, - i purp)ses, to employ dioxane where the cAtalyst is a mineral acid, or ethanol where an alkali metal hydroxide is used as the catalyst. While the reaction temperature varies with different catalysts that may be employed, the reaction is generally conducted at a temperature ranging from 0C to the boiling point of solvent used. It is particularly advantageous, in commercial runs, to carry out the reaction under reflux of the solvent employed.
~ he contemplated compound (I) thus ob'ained can be eas;ly separated and purified by conventional separatory I procedures such as extraction and recrystallization.
As a commercial production process, the method , according to the present invention has a number of advant-i ageous features, such as the reduced number of production steps required, improved product yields and greatly facili-tated reaction procedures.
Above anything else, the isolation and purification ¦ of intermediate compound (IV) and of end product compound (I) are considei~ably facilitated. For example, column chromatography and other complicated procedures may now ! be dispensed with.
¦ The following ~xsmples are further illustrative of the present invention, it being, of course, to be under-stood that the invention is by no means limited to such specific embodiments. In the following examples, gram(s) and milliliter(s) are simply abbreviated as "g." and 'lme.
' respectively.
. _ , ` ` ~ 1076139 l~;xample 1 To 300 m~. of dimethoxyethane was added 23.6 g of 4-benzoyl-l-indanone together with 22,0 g. OI tosylmethyl-isonitrile, The mixture was cooled to -10C and stirred, To this solutlon was added dropwise a solution of 22 g, of 28 /c sotLium methoxide in methanol diluted with 100 m~ of dimethoxy-ethane over a period of 1 hour, Following the dropwise addi-tion, the mixture was stirred at -10C for 1 hour and, then, a solution of 7 g, of scetic acid in 50 m~. of dimethoxy-ethane was added dropwise. The reaction mixture was con-centrated under reduced pressure and to the residue was added water, The mixture was extracted with chloroform, The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced ' -pressure, 'rO the residue was added 350 m~. OI benzene and, after incubation, the mixture was allowed to cool. The resultant crystals were collected by filtration. By the above procedure was obtained 33.4 g, (?7.5 %) of 4-benzoyl-l-~(N-formylamino)tosylmethylidene)indan, Recrystallization i - from ethanol yielded crystals melting at 230-232~C.
Elemental analysis, for C25H2104NS
Calcd. C, 69.58; H, 4.91; N, 3.25 Found C, 69.42; H, 4.92; N, 3.24 Examole 2 To 300 m~, of dimethox"-cthane was added 25.5 g. of ~? 4-(4-methylbenzoyl)-1-indanvne together with 22.4 g, of r' tosylmethylisonitrile, The mixt~re was cooled to -10C 1' . -- 7 --- 1~761~9 ~.
and stirred. To this solution was added dropwise a solution of 22,4 g. of 28 % sodium methoxide in methnnol diluted with 100 m~. of dimethoxyethane over a period of 1 hour, Following the dropwise addition, the mixture was stirred at -10C for 30 minutes and, then, a solution of 7,2 g. of acetic acid in 10 m~, of dimethoxyethane was added dropwise.
The reaction mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted with chloroform, The extract was washed with wster and dried over magnesium sulfate, The solvent was distilled off under reduced pressure. To the residue was added 500 m~. of ~ benzene and, after incubation, the mixture was allowed to ! cool. The resultant crystals were then collected by filtra-tion. By the above procedure was obtained 33,8 g. (74.4 %) of l-((N-formylamino)tosylmethylidene~-4-(4-methylbenzoyl)indan.
i Recrystallization from ethanol yielded crystals melting at t 200-204C.
~, Elemental analysis, for C26H2304NS
~ Cal^d, C, 70.10; H, 5,20; N, 3,14 ~ Found C, 70,15; H, 5.09; N, 3,14 t xample 3 To 30 m~. of dimethoxyethane was added 2,5 g, of 4-(4-methylbenzoyl)-1-indartone ~cgether with 2.2 g, of tosyl-methylisonitrile. The mixture was cooled to -10C and stirred, To this solution wa.s added dropwise a solution of sodium ethoxide (prepared from 250 mg, of sQdium metal and 3 m~, of dry ethanol) diluted with 10 m~, of dimethoxy-ethane over a period of 30 minutes, Following the dropwise ., _ ~; r 1076139 addition, the mixtur~ was stirred at - 5C for 1 hour and, then, a solution of 0.7 g, of acetic acid in 5 m~, of dimethoxy-ethane was added dropwise, The reaction mixture was concent- ;
rated under reduced pressure and to the residue was added water, The mixture was extracted with chloroform, The extract was washed with water and dried over magnesium ` sulfate, The solvent was then distilled off under reduced ; pressure, To the residue was added 50 m~, of benzene and, after incubation, the mixture waa allowed to cool, The resultant crystals were collected by filtration. By the above procedure was obtained 3,37 g. (75.7 %) of 1~
formylamino)tosylmethylidene)-4-(4-methylbenzoyl)indan, In spectral data, this product was found to be identical Witil the crystals obtained in Example 2.
Example 4 To 15 m~. of dry tetrahydrofuran was added 1,25 g. of , 4-(4-methylbenzoyl)-1-indanone together with 1,1 g, of i tosylmethylisonitrile. The mixture was cooled to -10C and ¦ stirred. To this solution was added dropwise a solution of 1.1 g, of 28 '~ sodium methoxide in methanol diluted with ~ 5 m~, of dry tetrahydrofuran over a period of 20 minutes.
j Following the dropwise addition, the mixture was stirred at -10C for 1 hour ar.d, then, a solution of 0,35 g, of acetic acid in 5 m~. of tetrahydrofuran was added dropwise, ~he reaction mixture was concentrated under reduced pressure ~ and to the residue was added water. The mixture was extracted ¦ with chloroform, The extract was washed with water and 3 dried over magnesium sulfate, The solvent was then distilled '':
) ~ .
off under reduced pressure. To the residue was added 25 m~.
of benzene and, after incubation, the mixture was allowed to cool. The resultant crystals were collected by filtra- -tion. 9y the above procedure was obtained 1.4 g. (64 /0) of l-((N-for~ylamino)tosylmethylidene)-4-(4-methylbenzoyl)-indan. In spectral data, this produc' was found to be identical with the crystals obtained in ~xample 2.
Example 5 ~o 20 ml. of dimethoxye~hane was added 1.8 g. of 4-(4-chlorobenzoyl)-1-indanone together with 1.5 g of tosyl-methylisonitrile. The mixture was cooled to -10C and stirred To this solution was added dropwise a solution of 1.5 g. of 28 % sodium methoxide in ~ethanol diluted with !
5 mf. of dimethoxyethane over a period of 15 minutes, j Following the dropwise addition, the mixture was stirred , at -10C for 1 nour and, then, a solution of 0.5 g. of ¦ acetic acid in 5 m~. of dimethoxyethane was added dropwise.
S The reaction mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate, ~he solvent was then distilled off under reduced pressure. ~o the residue was added 20 m~.
of benzene and, after incubation, the mixture was allowed to cool The resultant crystals were collected by filtra-tion.
~y the above procedure was obtained 2.45 g. (79.0 %) o of 4-(4-chlorobenzoyl)-l-((N-formylamino)tosylmethylidene)-- ~ indan. Recrystallization from ethanol yielded crystals . y , 7 613~9 melting at 185-188C.
Elemental analysis, for C25H2004NSC~
Calcd, C, 64,44; H, 4,33; N, 3.01; Cf, 7.61 ,' - Found C, 64.58; H, 4,39; N, 2.99; ce, 7.55 Ex~mDle 6 To 15 m~. of dimethoxyethane was added 1.25 g, of 6-chloro-5-cyclohexyl-1-indanone together with 1,1 g. of tosylmethylisonitrile. The mixture was cooled to -10C
and stirred, To this solution was added dropwise a solution of 1,1 g, of 28 % sodium methoxide in methanol diluted ~rith ) 5 me~ of dimethoxyethane over a period of 15 minutes, I After the dropwise addition h~d been completed, the mixture was stirred at -10C for 1 hour and, then, a solution of 0.35 g. of acetic acid in 5 mf. of dimethoxyethane was added dropwise. The reaction mixture was concentrated under ~ reduced pressure and to the residue was added water. The ¦ mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. ~ke residue was dissolved in 100 me. of ether under heating and filtered. The filtrate was allowed to cool, ana, ~e resultant crystals were collected by filtration. By the abovo procedure wa:; obtained 1.3 g. (71 ~o) of 6-chloro-5-cyclohexyl-l-~(N-formylamino)tosylmethylidene)indan, melting point: 195-199CC.
Elemental analysis, for C24H2603NSCe Calcd, C, 64,92; H, 5.90; N, 3,16 E r c, 64.94; H, 6.07; N, 3,15 -~
1o76139 ; i By a procedure similar to that described above, the following compound was synthesized. 5-Cyclohexyl-l-((N-- formylamino)tosylmethylidene)indan, melting point: 135-138C.
; Elemental analysis, for C24H270~NS
Calcd C, 70.38; H, 6.65; N, ~.42 Found C, 7G.05; H, 6.94; N, 3.39 ; Example 7 To 40 m~. of acetonitrile was added 2.36 g. of 4-benzoyl-l-indanone together with 2.3 g. of tosylmethyl-isonitrile. ~he mixture was cooled to -15C and stirred.
To this solution was added dropwise a solution of 2.2 g. of 28 % so~ium ~ethoxide in meth:nol over a period of 8 minutes ~. !
!' ' Following the dropwise addition, the mixture was stirred at -12 to -lO~C for 2 hours. After 0.7 g. of acetic acid ¦ - was added to the mixture, the solvent was distilled off under reduced pressure. To the residue was added water.
I The mixture was extracted with chloroform. ~he extract ¦ was washed with water and dried over ma~nesium sulfate.
- ¦ The solvent was then distilled off under reduced pressure.
~ To the residue was added 15 m~. of benzene and1 after ., ~
¦ incubation the mixture was allowed to cool. ~he resultant crystals were then collected by filtration.
By the above procedure was obtained 2.4 g. (56 %) of 4 benzoyl-l-~(N-formylemi.lo)tosylmethylidene)indan. In .
spectral data, this product was fo~nd to be iden.ical with tbe crystals obtained in ~xample~
.
- ~ Example 8 To 32 4 g. of 1-((N-formylamino)tosylmeth~Jlidene1-4-- 12 - _ (4-methylbenzoyl)indan was added 350 m~ of dioxane together with 350 m~. of concentrated hydrochloric acid and the - mixture was refluxed in an oil bath at 110C for 4 hours.
The reaction mixture was concentrated under reduced pressure and tG the residue was added water. ~he mixture was extracted with ether. ~he extract was washed with water and extracted twice with 200 m~. portions of a 5 % aqueous solution of potassi~ carbonate. ~he extracts were combined and washed with ether.
~ he extract was acidified with hydrochloric ac d and the p:ecipitate obtained was extracted with benzelle. The benzene layer was washed with water ard aqueous sodium chloride, dried over anhydrous sodium sulfate and, after additiGn of activated carbon, filtered. ~he filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of 50 me. of benzene and 150 m~ of cyclohexane.
; ~y the above procedure was obtained 15.6 g. (76.5 %) of 4-(4-methylbenzoyl)-1-indancarboxylic acid. Recr~stalli-zation from 4Q % aqueous ethanol yielded crystals melting at 133-135C.
Elemental analysis~ for C18H1603 Calcd C, 77.12; ~, 5.75 Found C, 77.18; H, 5.4~
Similarly, the following compounds were synthesizcd.
4--v~zoyl-1-indancarboxylic acid melting point: 101.5-103C; yield 75 ,~
j 4-(4-C~lorobenzoyl)-l-indancarboxylic acid _ melting poirt: 137.5-139.5~C; yield 78 %
r~
1076~3g 6-Chloro-5-cyclohexyl-1-indancarboxylic acid meltir~ point: 151-152C; yield 75 ,' xample 9 To 2,4 g. of 4-benzoyl-1-((N-foImylamino)tosylmethyl-idene~indan was added 15 me. of acetic acid to~ether with 15 m~. of concentrated hydrccil~oric acid and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and to the residue was ~dded water. The mlxture was extracted with benzene. The extract was washed with water and then extracted three times with 15 ml.
portions of a 5 k aqueous solutio~ of potassium carbonate.
The extracts were combined and decolored with activated carbon. The extract was acidified with hydrochloric acid and ex~racted three times with benzene. The benzene layer was washed with water and dried over magnesium sulfate.
~he solvent was distilled off under reduced pressure and the residue was recrystallized from a mixture of 2~5 ml.
of benzene and 7.5 me. of cyclohexane. By the ahove procedure was obtained 1.1 g. (7:; %) of 4-benzoyl-1-indan-carboxylic acid as crystals melting at 101-103C.
Example 1~
To 60 me. of dimethoxyethane was added 5.G g. of 4-(4-methylbenzoyl)- -indanone toge'uher with 4.4 g, of tosyl-methylisonitrile. The ~ixture was cooled to -10C ar.d stirred, ~o this solution was added dropwise a solution of 4.4 g. of 28 ,~ ~odiu~ methoxide in methanol diluted with 20 me. of dimethoxyethane over a period of - 14 _ 1C~76139 30 minutes. ~ollowing the dropwise addition, the mixture was stirred at -10C for 1 hour. The solvent was distil1ed off under reduced pressure and 100 m~. of dioxane and 100 mr.
of concentrated hydrochloric acid were added to the residue.
The mixture was refluxed for 4 hours, and the reaction mixture was concentrated under reduced pressure To the residue was added water. The mixture was extracted with benzene The extract was washed with water and then extracted with 5 /~ aqueous solution of po-tassium carbonate. The extract was washed with benzene and acidified with hydrochloric acid ar.d the precipitate obtained was extracted with benzene.
The benzene layer was washed with water and aqueous solution of sodium chloride, dried over sodium sulfate and, after ado~tion of activated carbon, filtered. The ~iltrate was r eoncentrated ~nd the residue was recrystallized from a 40 %
acueous ethanol By the sbove procedura was obtained 2.82 g (50 ,S) of 4-(4-~ethylbenzoyl~ dancarboxylic acid. In speetral data, this product was found to be identical with the crystals obtained in Example ~.
~ By a similar procedure to the above, 1.2 g. (50 %) ; ~ of 5-cyclohexyl~ dancarboxylic acid was obtained from `~ 2.1 g. of 5-eyclohexyl-1-indanone and 2.2 g.-of tosyl-~ met~ylisonitrile. Melti~g point: 140-144C.
.~ I
,, i , ,, I
~ 15 -,
~. Rl R ~ (I) wherein Rl represents a hydrogen atom, an arylcarbonyl group or an arylcarbonyl group substituted by alkyl ha~ing 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen; R2 is a hydrogen atom ~ or a cycloalkyl group; and R3 is a hydrogen atom or a halogen atom.
i The indan derivatives of general formula ~I) have eminent ¦ 10 analgesic, antiinfla~matory and antipyretic properties and are of value as, for example, analgesics, antiinflammatory agents, antipyretics and other agents in huoan or animal use. For the production of these compounds, there are known the processes disclosed in United States Patent 3,923,866 and United States Patent 3,953,500, for instance.
Hovever, such known processes are not altogether satisfactory in such aspects as production steps, yield purification procedure ` ', and so forth.
The present invention seeks to provide a novel method for producing the indan derivatives of the general formula (I~ which has advantsges from the industrial point of view.
Tho present invention therefore relates to a method for producing an indan derivative of general formula ~I), which comprises tl~ reacting z compound of general formula:
Rl R
<~
,,, '' ' '' i c; ~ 107~
~ , wherein Rl, R2 and 23 have the meanings given above, with a sulfonylmethyl-isonitrile compound of the general formula:
wherein R4 represents an alkyl group of 1 to 4 carbon atoms; an aryl group which i; unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, or an aralkyl group or an aralkyl which is substituted by alkyl of I to 4 carbon atoms; in the presence of a baso to produce a methylideneindan compound of the general formula:
~3/ ~ ~IV~
! lo wherein Rl, R2, R3 and R4 have the meanings given above, and then ¦ (2) hydrolyzing the once-recovered methylideneindan compound. , Referring to thc above general formulas, the aryl moiety ¦ of said arylcarbonyl group Rl may for example be phenyl or naphthyl.
¦ This aryl group ~ se ~ay also be substituted, the substituents ¦ including straight-chain or branchcd lower alkyl groups having 1 j to 4 carbon atoms te.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, ~, isobutyl, t-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms ~e.g. methoxy, eth^xy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, etc.), or ha.ogen ~e.g. fluorine, chlorine, bromine, etc.). One or more of such substituents, which may be the same or different groups, may occur in optional positions on v ~ I
.. , ~_ . --. .. . .
I
;h ~ ~,076139 ~. ,.
the aryl group. In the general formulas, the cycloalkyl group R2 is one containing 5 to 7 carbon atoms ~e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) As examples of said halogen atom represented by R3, there may be mentioned chlorine, bromine, fluorine and iodine. As examples of aryl group represented by R4, there may be mentioned phenyl and naphthyl. The aralkyl group represented by R4 may for example be benzyl, phenethyl or the like. The aryl and aralkyl groups may have substituents in optional positions on the respective aromatic rings, said substituents boing j 10 alkyl groups of 1 to 4 carbon atoms, namely methyl, ethyl, propyl or butyl. The alkyl group, also alternatively designated by R4, is an alkyl group containing 1 to 4 carbon atoms, thus being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl.
In the method according to the present invention, a compound of gcneral formula tll) is first reacted with a sulfonyl-methylisonitrile coopound tIII) in the presence of a base.
As examples of the base, there may be mentioned metol alkoxides te.g. alkali metal alkoxide prepared from lower alcohols such as methanol, ethanol, t-butanol, etc. and alkali metals such as 1 20 sodium, potassium and the liXe), alkali metal hydrides te.g. sodium hydride, lithium hydride, etc.) and so on. When metal alkoxide is used, it is normally nore expedient to use it as a solution in the corresponding alco~ol.
This reaction is preferably carried out in a solvent, which may for example be an ether (e.g. dimethoxyethane, diethoxy- r ethane, :etrahydrofuran, dioxane or the liXe~, nitrile (e.g. acetonitrile, propionitrile or the like), alkyl halide Ce.g. methylene chloride, ~ ~ 1076139 `~. ethylene chloride, methylene bromide or the like2 and so on.
Thi5 reaction is usually carried out at a temperature ranging from -70 to 10C, preferably at a temperature between ~ -S0~ and 0C and mcre preferably at a temperature betwcen ~ -20 and 0C, although the n,ost preferable temperature varies with the type of solvent and of base employed and other conditions.
The aforesaid base is preferably used in a proportion of 1 to 1.5 moles per mole of compound (II), while said sulfonylmethylisonitrile f ~:~
:~"' .. - ,' ' I ' i " ~ .
"'~''''' . I "
,' ~ ~i ~
, i ~.
, : ' .,-~,., ... ,~,.......... ~ , .. ~ '' - 10761~3$
. .
compound (III) is preferably employed in an equimolar proportion relative to the base ~he resultant compound (IV) can be easily separated and purified by conventional separatory procedure~ such as extraction, recrystullization and so forth. While compound (IV) is normally o~tained as a mixture of two stereoisomers, it is generally a enable to crystallization and, as such a mixture, can be easily purified However, for the purpose of obtaining a compound (I), the compound (IV) need not necessarily be purified but the crude product once recovered may be direct]y sub-Jected to the next reaction ~or example, the residue which is obtained by the conce~tration of the reaction mixture can be employed to the next reaction. ~ 1 Then, the compound of general formula (IV) is hydro- , lyzed. The catalyst for hydrolysis may be whichever of an acid catalyst and a basic catalyst. As examples of the acid catalyst, there may be mentioned mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phos-phoric acid, etc., while said basic catalyst may for example be selected from among alkali metal hydroxides such as sodium h~droxide, potassium hydroxide and so forth.
While water alone may prove to be a useful solvent, the reaction time may be considerably reduced by the concurrent use of one of water-miscible ethers (e.g dioxane, tetra-hydrofurar., dimethoxyethane, diethoxyethane, etc ), w&~er- ~ !
miscible alcohols (e.g. methanol, ethanol, t-butanol, etc.) and water-miscible organic acids (e.g. acetic acid, propionic acid, e~^ ) It is particularly advantageous, for commercial . . , j, - i purp)ses, to employ dioxane where the cAtalyst is a mineral acid, or ethanol where an alkali metal hydroxide is used as the catalyst. While the reaction temperature varies with different catalysts that may be employed, the reaction is generally conducted at a temperature ranging from 0C to the boiling point of solvent used. It is particularly advantageous, in commercial runs, to carry out the reaction under reflux of the solvent employed.
~ he contemplated compound (I) thus ob'ained can be eas;ly separated and purified by conventional separatory I procedures such as extraction and recrystallization.
As a commercial production process, the method , according to the present invention has a number of advant-i ageous features, such as the reduced number of production steps required, improved product yields and greatly facili-tated reaction procedures.
Above anything else, the isolation and purification ¦ of intermediate compound (IV) and of end product compound (I) are considei~ably facilitated. For example, column chromatography and other complicated procedures may now ! be dispensed with.
¦ The following ~xsmples are further illustrative of the present invention, it being, of course, to be under-stood that the invention is by no means limited to such specific embodiments. In the following examples, gram(s) and milliliter(s) are simply abbreviated as "g." and 'lme.
' respectively.
. _ , ` ` ~ 1076139 l~;xample 1 To 300 m~. of dimethoxyethane was added 23.6 g of 4-benzoyl-l-indanone together with 22,0 g. OI tosylmethyl-isonitrile, The mixture was cooled to -10C and stirred, To this solutlon was added dropwise a solution of 22 g, of 28 /c sotLium methoxide in methanol diluted with 100 m~ of dimethoxy-ethane over a period of 1 hour, Following the dropwise addi-tion, the mixture was stirred at -10C for 1 hour and, then, a solution of 7 g, of scetic acid in 50 m~. of dimethoxy-ethane was added dropwise. The reaction mixture was con-centrated under reduced pressure and to the residue was added water, The mixture was extracted with chloroform, The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced ' -pressure, 'rO the residue was added 350 m~. OI benzene and, after incubation, the mixture was allowed to cool. The resultant crystals were collected by filtration. By the above procedure was obtained 33.4 g, (?7.5 %) of 4-benzoyl-l-~(N-formylamino)tosylmethylidene)indan, Recrystallization i - from ethanol yielded crystals melting at 230-232~C.
Elemental analysis, for C25H2104NS
Calcd. C, 69.58; H, 4.91; N, 3.25 Found C, 69.42; H, 4.92; N, 3.24 Examole 2 To 300 m~, of dimethox"-cthane was added 25.5 g. of ~? 4-(4-methylbenzoyl)-1-indanvne together with 22.4 g, of r' tosylmethylisonitrile, The mixt~re was cooled to -10C 1' . -- 7 --- 1~761~9 ~.
and stirred. To this solution was added dropwise a solution of 22,4 g. of 28 % sodium methoxide in methnnol diluted with 100 m~. of dimethoxyethane over a period of 1 hour, Following the dropwise addition, the mixture was stirred at -10C for 30 minutes and, then, a solution of 7,2 g. of acetic acid in 10 m~, of dimethoxyethane was added dropwise.
The reaction mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted with chloroform, The extract was washed with wster and dried over magnesium sulfate, The solvent was distilled off under reduced pressure. To the residue was added 500 m~. of ~ benzene and, after incubation, the mixture was allowed to ! cool. The resultant crystals were then collected by filtra-tion. By the above procedure was obtained 33,8 g. (74.4 %) of l-((N-formylamino)tosylmethylidene~-4-(4-methylbenzoyl)indan.
i Recrystallization from ethanol yielded crystals melting at t 200-204C.
~, Elemental analysis, for C26H2304NS
~ Cal^d, C, 70.10; H, 5,20; N, 3,14 ~ Found C, 70,15; H, 5.09; N, 3,14 t xample 3 To 30 m~. of dimethoxyethane was added 2,5 g, of 4-(4-methylbenzoyl)-1-indartone ~cgether with 2.2 g, of tosyl-methylisonitrile. The mixture was cooled to -10C and stirred, To this solution wa.s added dropwise a solution of sodium ethoxide (prepared from 250 mg, of sQdium metal and 3 m~, of dry ethanol) diluted with 10 m~, of dimethoxy-ethane over a period of 30 minutes, Following the dropwise ., _ ~; r 1076139 addition, the mixtur~ was stirred at - 5C for 1 hour and, then, a solution of 0.7 g, of acetic acid in 5 m~, of dimethoxy-ethane was added dropwise, The reaction mixture was concent- ;
rated under reduced pressure and to the residue was added water, The mixture was extracted with chloroform, The extract was washed with water and dried over magnesium ` sulfate, The solvent was then distilled off under reduced ; pressure, To the residue was added 50 m~, of benzene and, after incubation, the mixture waa allowed to cool, The resultant crystals were collected by filtration. By the above procedure was obtained 3,37 g. (75.7 %) of 1~
formylamino)tosylmethylidene)-4-(4-methylbenzoyl)indan, In spectral data, this product was found to be identical Witil the crystals obtained in Example 2.
Example 4 To 15 m~. of dry tetrahydrofuran was added 1,25 g. of , 4-(4-methylbenzoyl)-1-indanone together with 1,1 g, of i tosylmethylisonitrile. The mixture was cooled to -10C and ¦ stirred. To this solution was added dropwise a solution of 1.1 g, of 28 '~ sodium methoxide in methanol diluted with ~ 5 m~, of dry tetrahydrofuran over a period of 20 minutes.
j Following the dropwise addition, the mixture was stirred at -10C for 1 hour ar.d, then, a solution of 0,35 g, of acetic acid in 5 m~. of tetrahydrofuran was added dropwise, ~he reaction mixture was concentrated under reduced pressure ~ and to the residue was added water. The mixture was extracted ¦ with chloroform, The extract was washed with water and 3 dried over magnesium sulfate, The solvent was then distilled '':
) ~ .
off under reduced pressure. To the residue was added 25 m~.
of benzene and, after incubation, the mixture was allowed to cool. The resultant crystals were collected by filtra- -tion. 9y the above procedure was obtained 1.4 g. (64 /0) of l-((N-for~ylamino)tosylmethylidene)-4-(4-methylbenzoyl)-indan. In spectral data, this produc' was found to be identical with the crystals obtained in ~xample 2.
Example 5 ~o 20 ml. of dimethoxye~hane was added 1.8 g. of 4-(4-chlorobenzoyl)-1-indanone together with 1.5 g of tosyl-methylisonitrile. The mixture was cooled to -10C and stirred To this solution was added dropwise a solution of 1.5 g. of 28 % sodium methoxide in ~ethanol diluted with !
5 mf. of dimethoxyethane over a period of 15 minutes, j Following the dropwise addition, the mixture was stirred , at -10C for 1 nour and, then, a solution of 0.5 g. of ¦ acetic acid in 5 m~. of dimethoxyethane was added dropwise.
S The reaction mixture was concentrated under reduced pressure and to the residue was added water. The mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate, ~he solvent was then distilled off under reduced pressure. ~o the residue was added 20 m~.
of benzene and, after incubation, the mixture was allowed to cool The resultant crystals were collected by filtra-tion.
~y the above procedure was obtained 2.45 g. (79.0 %) o of 4-(4-chlorobenzoyl)-l-((N-formylamino)tosylmethylidene)-- ~ indan. Recrystallization from ethanol yielded crystals . y , 7 613~9 melting at 185-188C.
Elemental analysis, for C25H2004NSC~
Calcd, C, 64,44; H, 4,33; N, 3.01; Cf, 7.61 ,' - Found C, 64.58; H, 4,39; N, 2.99; ce, 7.55 Ex~mDle 6 To 15 m~. of dimethoxyethane was added 1.25 g, of 6-chloro-5-cyclohexyl-1-indanone together with 1,1 g. of tosylmethylisonitrile. The mixture was cooled to -10C
and stirred, To this solution was added dropwise a solution of 1,1 g, of 28 % sodium methoxide in methanol diluted ~rith ) 5 me~ of dimethoxyethane over a period of 15 minutes, I After the dropwise addition h~d been completed, the mixture was stirred at -10C for 1 hour and, then, a solution of 0.35 g. of acetic acid in 5 mf. of dimethoxyethane was added dropwise. The reaction mixture was concentrated under ~ reduced pressure and to the residue was added water. The ¦ mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. ~ke residue was dissolved in 100 me. of ether under heating and filtered. The filtrate was allowed to cool, ana, ~e resultant crystals were collected by filtration. By the abovo procedure wa:; obtained 1.3 g. (71 ~o) of 6-chloro-5-cyclohexyl-l-~(N-formylamino)tosylmethylidene)indan, melting point: 195-199CC.
Elemental analysis, for C24H2603NSCe Calcd, C, 64,92; H, 5.90; N, 3,16 E r c, 64.94; H, 6.07; N, 3,15 -~
1o76139 ; i By a procedure similar to that described above, the following compound was synthesized. 5-Cyclohexyl-l-((N-- formylamino)tosylmethylidene)indan, melting point: 135-138C.
; Elemental analysis, for C24H270~NS
Calcd C, 70.38; H, 6.65; N, ~.42 Found C, 7G.05; H, 6.94; N, 3.39 ; Example 7 To 40 m~. of acetonitrile was added 2.36 g. of 4-benzoyl-l-indanone together with 2.3 g. of tosylmethyl-isonitrile. ~he mixture was cooled to -15C and stirred.
To this solution was added dropwise a solution of 2.2 g. of 28 % so~ium ~ethoxide in meth:nol over a period of 8 minutes ~. !
!' ' Following the dropwise addition, the mixture was stirred at -12 to -lO~C for 2 hours. After 0.7 g. of acetic acid ¦ - was added to the mixture, the solvent was distilled off under reduced pressure. To the residue was added water.
I The mixture was extracted with chloroform. ~he extract ¦ was washed with water and dried over ma~nesium sulfate.
- ¦ The solvent was then distilled off under reduced pressure.
~ To the residue was added 15 m~. of benzene and1 after ., ~
¦ incubation the mixture was allowed to cool. ~he resultant crystals were then collected by filtration.
By the above procedure was obtained 2.4 g. (56 %) of 4 benzoyl-l-~(N-formylemi.lo)tosylmethylidene)indan. In .
spectral data, this product was fo~nd to be iden.ical with tbe crystals obtained in ~xample~
.
- ~ Example 8 To 32 4 g. of 1-((N-formylamino)tosylmeth~Jlidene1-4-- 12 - _ (4-methylbenzoyl)indan was added 350 m~ of dioxane together with 350 m~. of concentrated hydrochloric acid and the - mixture was refluxed in an oil bath at 110C for 4 hours.
The reaction mixture was concentrated under reduced pressure and tG the residue was added water. ~he mixture was extracted with ether. ~he extract was washed with water and extracted twice with 200 m~. portions of a 5 % aqueous solution of potassi~ carbonate. ~he extracts were combined and washed with ether.
~ he extract was acidified with hydrochloric ac d and the p:ecipitate obtained was extracted with benzelle. The benzene layer was washed with water ard aqueous sodium chloride, dried over anhydrous sodium sulfate and, after additiGn of activated carbon, filtered. ~he filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of 50 me. of benzene and 150 m~ of cyclohexane.
; ~y the above procedure was obtained 15.6 g. (76.5 %) of 4-(4-methylbenzoyl)-1-indancarboxylic acid. Recr~stalli-zation from 4Q % aqueous ethanol yielded crystals melting at 133-135C.
Elemental analysis~ for C18H1603 Calcd C, 77.12; ~, 5.75 Found C, 77.18; H, 5.4~
Similarly, the following compounds were synthesizcd.
4--v~zoyl-1-indancarboxylic acid melting point: 101.5-103C; yield 75 ,~
j 4-(4-C~lorobenzoyl)-l-indancarboxylic acid _ melting poirt: 137.5-139.5~C; yield 78 %
r~
1076~3g 6-Chloro-5-cyclohexyl-1-indancarboxylic acid meltir~ point: 151-152C; yield 75 ,' xample 9 To 2,4 g. of 4-benzoyl-1-((N-foImylamino)tosylmethyl-idene~indan was added 15 me. of acetic acid to~ether with 15 m~. of concentrated hydrccil~oric acid and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and to the residue was ~dded water. The mlxture was extracted with benzene. The extract was washed with water and then extracted three times with 15 ml.
portions of a 5 k aqueous solutio~ of potassium carbonate.
The extracts were combined and decolored with activated carbon. The extract was acidified with hydrochloric acid and ex~racted three times with benzene. The benzene layer was washed with water and dried over magnesium sulfate.
~he solvent was distilled off under reduced pressure and the residue was recrystallized from a mixture of 2~5 ml.
of benzene and 7.5 me. of cyclohexane. By the ahove procedure was obtained 1.1 g. (7:; %) of 4-benzoyl-1-indan-carboxylic acid as crystals melting at 101-103C.
Example 1~
To 60 me. of dimethoxyethane was added 5.G g. of 4-(4-methylbenzoyl)- -indanone toge'uher with 4.4 g, of tosyl-methylisonitrile. The ~ixture was cooled to -10C ar.d stirred, ~o this solution was added dropwise a solution of 4.4 g. of 28 ,~ ~odiu~ methoxide in methanol diluted with 20 me. of dimethoxyethane over a period of - 14 _ 1C~76139 30 minutes. ~ollowing the dropwise addition, the mixture was stirred at -10C for 1 hour. The solvent was distil1ed off under reduced pressure and 100 m~. of dioxane and 100 mr.
of concentrated hydrochloric acid were added to the residue.
The mixture was refluxed for 4 hours, and the reaction mixture was concentrated under reduced pressure To the residue was added water. The mixture was extracted with benzene The extract was washed with water and then extracted with 5 /~ aqueous solution of po-tassium carbonate. The extract was washed with benzene and acidified with hydrochloric acid ar.d the precipitate obtained was extracted with benzene.
The benzene layer was washed with water and aqueous solution of sodium chloride, dried over sodium sulfate and, after ado~tion of activated carbon, filtered. The ~iltrate was r eoncentrated ~nd the residue was recrystallized from a 40 %
acueous ethanol By the sbove procedura was obtained 2.82 g (50 ,S) of 4-(4-~ethylbenzoyl~ dancarboxylic acid. In speetral data, this product was found to be identical with the crystals obtained in Example ~.
~ By a similar procedure to the above, 1.2 g. (50 %) ; ~ of 5-cyclohexyl~ dancarboxylic acid was obtained from `~ 2.1 g. of 5-eyclohexyl-1-indanone and 2.2 g.-of tosyl-~ met~ylisonitrile. Melti~g point: 140-144C.
.~ I
,, i , ,, I
~ 15 -,
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of producing an indan derivative of the general formula:
wherein R1 represents a hydrogen atom, an arylcarbonyl group or an arylcarbonyl group substituted by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen; R2 is a hydrogen atom or a cycloalkyl group having 5 to 7 carbon atoms; and R3 is a hydrogen atom or a halogen atom, which comprises (1) reacting a compound of the general formula:
wherein R1, R2 and R3 have the meanings given above, with a sulfonyl-methylisonitrile compound of the general formula:
wherein R4 represents an alkyl group of 1 to 4 carbon atoms, an aryl group which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, or an aralkyl group or an aralkyl which is substituted by alkyl of 1 to 4 carbon atoms; in the presence of a base to produce a methylideneindan compound of the general formula:
wherein R1, R2, R3 and R4 have the meanings given above, and then (2) hydrolyzing the once-recovered methylindene-indan compound.
wherein R1 represents a hydrogen atom, an arylcarbonyl group or an arylcarbonyl group substituted by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen; R2 is a hydrogen atom or a cycloalkyl group having 5 to 7 carbon atoms; and R3 is a hydrogen atom or a halogen atom, which comprises (1) reacting a compound of the general formula:
wherein R1, R2 and R3 have the meanings given above, with a sulfonyl-methylisonitrile compound of the general formula:
wherein R4 represents an alkyl group of 1 to 4 carbon atoms, an aryl group which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, or an aralkyl group or an aralkyl which is substituted by alkyl of 1 to 4 carbon atoms; in the presence of a base to produce a methylideneindan compound of the general formula:
wherein R1, R2, R3 and R4 have the meanings given above, and then (2) hydrolyzing the once-recovered methylindene-indan compound.
2. A method as claimed in claim 1, wherein the reaction of the step (1) is carried out at a temperature ranging from 10 to -70°C.
3. A method as claimed in claim 1, wherein the base used in the step (1) is an alkali metal alkoxide.
4. A method as claimed in claim 1, wherein the reaction of the step (1) is carried out in the presence of an organic solvent.
5. A method as claimed in claim 4, wherein the organic solvent is an ether, nitrile or alkylhalide.
6. A method as claimed in claim 1, wherein the reaction of the step (2) is carried out in the presence of an acid or a base.
7. A method as claimed in claim 1, wherein the reaction of the step (2) is carried out at a temperature ranging from 0°C to the boiling, point of the solvent employed.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50152358A JPS6012341B2 (en) | 1975-12-19 | 1975-12-19 | Method for producing indane derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076139A true CA1076139A (en) | 1980-04-22 |
Family
ID=15538786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA268,042A Expired CA1076139A (en) | 1975-12-19 | 1976-12-16 | Method of producing indan derivatives |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS6012341B2 (en) |
| AT (1) | AT346837B (en) |
| AU (1) | AU505609B2 (en) |
| BE (1) | BE849561A (en) |
| CA (1) | CA1076139A (en) |
| CH (1) | CH603534A5 (en) |
| DE (1) | DE2656784A1 (en) |
| DK (1) | DK568476A (en) |
| ES (1) | ES454292A1 (en) |
| FI (1) | FI62049C (en) |
| FR (1) | FR2336371A1 (en) |
| GB (1) | GB1537906A (en) |
| GR (1) | GR62073B (en) |
| HU (1) | HU171842B (en) |
| MX (1) | MX3741E (en) |
| NL (1) | NL7614110A (en) |
| NO (1) | NO764290L (en) |
| SE (1) | SE419213B (en) |
| SU (1) | SU667127A3 (en) |
| ZA (1) | ZA767225B (en) |
-
1975
- 1975-12-19 JP JP50152358A patent/JPS6012341B2/en not_active Expired
-
1976
- 1976-12-03 ZA ZA767225A patent/ZA767225B/en unknown
- 1976-12-07 AT AT905576A patent/AT346837B/en not_active IP Right Cessation
- 1976-12-08 MX MX765197U patent/MX3741E/en unknown
- 1976-12-13 HU HU76TA00001420A patent/HU171842B/en unknown
- 1976-12-13 GB GB51889/76A patent/GB1537906A/en not_active Expired
- 1976-12-14 AU AU20553/76A patent/AU505609B2/en not_active Expired
- 1976-12-14 GR GR52398A patent/GR62073B/en unknown
- 1976-12-15 DE DE19762656784 patent/DE2656784A1/en not_active Withdrawn
- 1976-12-16 SE SE7614169A patent/SE419213B/en unknown
- 1976-12-16 ES ES454292A patent/ES454292A1/en not_active Expired
- 1976-12-16 CA CA268,042A patent/CA1076139A/en not_active Expired
- 1976-12-17 NO NO764290A patent/NO764290L/no unknown
- 1976-12-17 BE BE173403A patent/BE849561A/en not_active IP Right Cessation
- 1976-12-17 FI FI763625A patent/FI62049C/en not_active IP Right Cessation
- 1976-12-17 CH CH1594676A patent/CH603534A5/xx not_active IP Right Cessation
- 1976-12-17 NL NL7614110A patent/NL7614110A/en not_active Application Discontinuation
- 1976-12-17 SU SU762429706A patent/SU667127A3/en active
- 1976-12-17 FR FR7638182A patent/FR2336371A1/en active Granted
- 1976-12-17 DK DK568476A patent/DK568476A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI62049B (en) | 1982-07-30 |
| JPS5277044A (en) | 1977-06-29 |
| ATA905576A (en) | 1978-04-15 |
| ZA767225B (en) | 1977-11-30 |
| NO764290L (en) | 1977-06-21 |
| AT346837B (en) | 1978-11-27 |
| FR2336371B1 (en) | 1980-05-16 |
| FR2336371A1 (en) | 1977-07-22 |
| MX3741E (en) | 1981-06-05 |
| NL7614110A (en) | 1977-06-21 |
| CH603534A5 (en) | 1978-08-31 |
| SU667127A3 (en) | 1979-06-05 |
| FI763625A (en) | 1977-06-20 |
| ES454292A1 (en) | 1977-12-16 |
| SE419213B (en) | 1981-07-20 |
| DE2656784A1 (en) | 1977-06-30 |
| DK568476A (en) | 1977-06-20 |
| SE7614169L (en) | 1977-06-20 |
| GB1537906A (en) | 1979-01-10 |
| FI62049C (en) | 1982-11-10 |
| GR62073B (en) | 1979-02-20 |
| JPS6012341B2 (en) | 1985-04-01 |
| HU171842B (en) | 1978-03-28 |
| AU2055376A (en) | 1978-06-22 |
| AU505609B2 (en) | 1979-11-29 |
| BE849561A (en) | 1977-06-17 |
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