CA1148539A - Amino-substituted tetracyclic compounds - Google Patents
Amino-substituted tetracyclic compoundsInfo
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- CA1148539A CA1148539A CA000318927A CA318927A CA1148539A CA 1148539 A CA1148539 A CA 1148539A CA 000318927 A CA000318927 A CA 000318927A CA 318927 A CA318927 A CA 318927A CA 1148539 A CA1148539 A CA 1148539A
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Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of a compound of the general formula:
XII
or a salt ester thereof, wherein X stands for oxygen, sulphur, the group or the group -CH2-;
R7 stands for hydrogen or C1-4 alkyl; and n is one or two, which comprises either:-(a) hydrolysing or alcoholysing a compound of the formula:
XIII
or a corresponding amide, wherein rings A and B, n and X are as previously defined; or (b) reacting an organometallic compound of the formula:
M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained or (c) hydrogenating a corresponding 3,4-dihydro compound, and when a free acid of formula I is required hydrolysing a corresponding ester.
The compounds so produced are useful as intermediates in the synthesis of compounds having useful pharmacological properties.
This invention relates to a process for the preparation of a compound of the general formula:
XII
or a salt ester thereof, wherein X stands for oxygen, sulphur, the group or the group -CH2-;
R7 stands for hydrogen or C1-4 alkyl; and n is one or two, which comprises either:-(a) hydrolysing or alcoholysing a compound of the formula:
XIII
or a corresponding amide, wherein rings A and B, n and X are as previously defined; or (b) reacting an organometallic compound of the formula:
M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained or (c) hydrogenating a corresponding 3,4-dihydro compound, and when a free acid of formula I is required hydrolysing a corresponding ester.
The compounds so produced are useful as intermediates in the synthesis of compounds having useful pharmacological properties.
Description
114853~
This application is a divisional of our copending Canadian Patent Application No. 199,996 filed May 15, 1974.
In our copending Canadian application number 199,996, certain compounds were disclosed which possess valuable C.N.S. activities, but at the same time exhibited exceedingly low toxicity. These compounds are of the general formula I:
/ R~
(CH2)n N
R6 ~
as well as the pharmaceutically acceptable salts thereof, in which X stands for oxygen, sulphur, the group NR7 or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 represent hydrogen, alkyl (1-4) which are either unsubstituted or substituted by a phenyl group, or the group -NR5R6 together represents a morpholino, piperidino or pyrrolidino group;
R7 stands for hydrogen or methyl;
n is the number 0, 1 or 2 and the dotted line means an optional C-C bond when n is zero.
D
The present invention relates to intermediates useful in the synthesis of compounds of formula I. Such intermediates are compounds of the general formula XII:
XII
(CH2)n-1 - COOH
or a salt or ester thereof; wherein X stands for oxygen, sulphur, the group NR7 or the group-CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R7 stands for hydrogen or ~ethyl; and n is one or two.
The invention also relates to a process for the preparation of a compound of formula XII, which comprises either:-(a) hydrolysing or alcoholysing a compound of the formula:
XIII
(CH2)n-1 CN
or a corresponding amide, wherein ring A, ring B, n and X are as previously i ~ - 2 -11~8539 defined; or (b) reacting an organometallic compound of the formula:
M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained or;
(c) hydrogenating a corresponding 3,4-dihydro compound;
and when a free acid of formula XII is required hydrolysing a corresponding ester.
Thus as indicated above the compounds of formula XII can be prepared by various methods, a number of which are described below.
In one method, the starting material is of general formula II:
II
1 >
in which ring A, ring B and X have the meanings mentioned above, and which is described and claimed in our copending Canadian application 318,926 filed concurrently (26227-34D).
The compounds of formula II are conveniently prepared by condensing a compound of general formula III:
~ III
D _ 3 with methyl vinyl ketone.
The keto group of compound II is reduced to a hydroxyl group, preferably with metal hydrides such as LiAlH4, diborane or in particular NaBH4. This hydroxyl group is then converted into the cyano group in a conventional manner, for instance by reaction with SOC12, PC15, PBr3, followed by reaction with a metal cyanide etc., resulting in a compound of the general formula IV.
~3 (CH2)n-1 ~ CN
in which ring A, ring B and X have the meanings specified before, and n is one.
The conversion to a compound of formula XIII can be performed in the usual way, for instance by treating a corresponding halide with a cyanide such as potassium- or sodium cyanide. The cyano group in the compound thus obtained can then be hydrolysed to the corresponding carboxyl group. An extension of the alkyl chain can be performed by reducing the carboxyl compound to afford the hydroxy-methyl compound.
The hydroxy-methyl compound thus obtained is converted into a compound in which the hydroxyl group is replaced by a leaving group, and repeating the above-mentioned cyanide reaction.
Compounds of formula XII can also be prepared by a Wittig reaction, a Wittig-Horner reaction or a Reformatski reaction. The starting material is a keto compound of formula II. Reagents necessary in these reactions are well-known and described in any chemical handbook, for example:
Ph3P=CH-B ~Wittig), (Eto)2-P~-3~ 0)-CH2-COR' in NaH and a suitable solvent (Wittig-Horner) and, BrZn-CH2-COR' (Reformatski), whereby Ph stands for an aryl group, in particular a phenyl group, B
represents a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or a hydroxyl group, and R' stands for an alkoxy group. An additional reaction may then be necessary to convert these moieties into a carboxyl group. It may also be necessary to reduce the double bond (/\1,2) formed pursuant to these reactions by means of a catalytic hydrogenation in order to obtain a compound of formula XII.
Compounds of formula XII when n = 1 can further be prepared by treating an organometallic compound of the following formula, M Hal fD 5 _ when ring A, ring B, and X have the meanings specified before, Hal represents a halogen atom, in particular iodine, and M represents a metal atom, in particuliarmagnesiUm, with C02, and subsequently decomposing the organometallic complex so obtained.
Esters of the compound XII are derived from aliphatic, cycloaliphatic, aromatic or araliphatic alcohols with 1-18 carbon atoms, which may be substituted by hydroxy or halogen groups, especially lower aliphatic alcohols with 1-6 carbon atoms, or phenylaliphatic alcohols with 7-10 C-atoms, such as methanol, ethanol, isopropanol, butanol, hexanol, phenethylalcohol, benzylalcohol, phenylpropylalcohol, p-chlorobenzylalcohol, p-hydroxyphenethylalcohol, etc.
The novel compounds of the formula XII may be isolated from the reaction mixture in the form of a pharmaceutically acceptable acid addition salt when X is the group / NR7, dependent upon the conditions in which the reaction is carried out. The acid addition salts may also be obtained by treating the free base with a pharmaceutically acceptable organic or inorganic acid. Acids that can be used in this connection are: hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicyclic acid or benzoic acid.
The compounds according to this invention contain an asymmetric carbon at position 2 of the tetracyclic molecule. By resolving these compounds or a starting product in their synthesis, the optical isomers can also be obtained in a direct way.
iD
1~48539 In the Examples the following nomenclature and numbering has been used:
~ C ~ 11 1, 2, 3, 4-tetrahydro-9H-6 ~ 2 tribenzo (b,d,f)-cyclohepta-~ ~ I triene 7 ~ X ~ 11 X = O or S
6 ~ 12 1, 2, 3, 4-tetrahydro-tribenzo ~ ~ I (b,d,f)-oxepine or -thiepine 7 ~ N ~ 11 6 ~ 12 1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine g~
By way of example the preparation of various starting products is disclosed. The preparation of analogous starting products proceeds in exactly the same way.
Example 1 6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine are added to a suspension of 3.7 g of lithium aluminium hydride in 300 ml of dry ether.
After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension obtained is filtered off and after 11~8539 that the filtrate is dried and e~aporated to dryness to obtain 2-hydroxy-l, , 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine.
This application is a divisional of our copending Canadian Patent Application No. 199,996 filed May 15, 1974.
In our copending Canadian application number 199,996, certain compounds were disclosed which possess valuable C.N.S. activities, but at the same time exhibited exceedingly low toxicity. These compounds are of the general formula I:
/ R~
(CH2)n N
R6 ~
as well as the pharmaceutically acceptable salts thereof, in which X stands for oxygen, sulphur, the group NR7 or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R5 and R6 represent hydrogen, alkyl (1-4) which are either unsubstituted or substituted by a phenyl group, or the group -NR5R6 together represents a morpholino, piperidino or pyrrolidino group;
R7 stands for hydrogen or methyl;
n is the number 0, 1 or 2 and the dotted line means an optional C-C bond when n is zero.
D
The present invention relates to intermediates useful in the synthesis of compounds of formula I. Such intermediates are compounds of the general formula XII:
XII
(CH2)n-1 - COOH
or a salt or ester thereof; wherein X stands for oxygen, sulphur, the group NR7 or the group-CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11- and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R7 stands for hydrogen or ~ethyl; and n is one or two.
The invention also relates to a process for the preparation of a compound of formula XII, which comprises either:-(a) hydrolysing or alcoholysing a compound of the formula:
XIII
(CH2)n-1 CN
or a corresponding amide, wherein ring A, ring B, n and X are as previously i ~ - 2 -11~8539 defined; or (b) reacting an organometallic compound of the formula:
M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained or;
(c) hydrogenating a corresponding 3,4-dihydro compound;
and when a free acid of formula XII is required hydrolysing a corresponding ester.
Thus as indicated above the compounds of formula XII can be prepared by various methods, a number of which are described below.
In one method, the starting material is of general formula II:
II
1 >
in which ring A, ring B and X have the meanings mentioned above, and which is described and claimed in our copending Canadian application 318,926 filed concurrently (26227-34D).
The compounds of formula II are conveniently prepared by condensing a compound of general formula III:
~ III
D _ 3 with methyl vinyl ketone.
The keto group of compound II is reduced to a hydroxyl group, preferably with metal hydrides such as LiAlH4, diborane or in particular NaBH4. This hydroxyl group is then converted into the cyano group in a conventional manner, for instance by reaction with SOC12, PC15, PBr3, followed by reaction with a metal cyanide etc., resulting in a compound of the general formula IV.
~3 (CH2)n-1 ~ CN
in which ring A, ring B and X have the meanings specified before, and n is one.
The conversion to a compound of formula XIII can be performed in the usual way, for instance by treating a corresponding halide with a cyanide such as potassium- or sodium cyanide. The cyano group in the compound thus obtained can then be hydrolysed to the corresponding carboxyl group. An extension of the alkyl chain can be performed by reducing the carboxyl compound to afford the hydroxy-methyl compound.
The hydroxy-methyl compound thus obtained is converted into a compound in which the hydroxyl group is replaced by a leaving group, and repeating the above-mentioned cyanide reaction.
Compounds of formula XII can also be prepared by a Wittig reaction, a Wittig-Horner reaction or a Reformatski reaction. The starting material is a keto compound of formula II. Reagents necessary in these reactions are well-known and described in any chemical handbook, for example:
Ph3P=CH-B ~Wittig), (Eto)2-P~-3~ 0)-CH2-COR' in NaH and a suitable solvent (Wittig-Horner) and, BrZn-CH2-COR' (Reformatski), whereby Ph stands for an aryl group, in particular a phenyl group, B
represents a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or a hydroxyl group, and R' stands for an alkoxy group. An additional reaction may then be necessary to convert these moieties into a carboxyl group. It may also be necessary to reduce the double bond (/\1,2) formed pursuant to these reactions by means of a catalytic hydrogenation in order to obtain a compound of formula XII.
Compounds of formula XII when n = 1 can further be prepared by treating an organometallic compound of the following formula, M Hal fD 5 _ when ring A, ring B, and X have the meanings specified before, Hal represents a halogen atom, in particular iodine, and M represents a metal atom, in particuliarmagnesiUm, with C02, and subsequently decomposing the organometallic complex so obtained.
Esters of the compound XII are derived from aliphatic, cycloaliphatic, aromatic or araliphatic alcohols with 1-18 carbon atoms, which may be substituted by hydroxy or halogen groups, especially lower aliphatic alcohols with 1-6 carbon atoms, or phenylaliphatic alcohols with 7-10 C-atoms, such as methanol, ethanol, isopropanol, butanol, hexanol, phenethylalcohol, benzylalcohol, phenylpropylalcohol, p-chlorobenzylalcohol, p-hydroxyphenethylalcohol, etc.
The novel compounds of the formula XII may be isolated from the reaction mixture in the form of a pharmaceutically acceptable acid addition salt when X is the group / NR7, dependent upon the conditions in which the reaction is carried out. The acid addition salts may also be obtained by treating the free base with a pharmaceutically acceptable organic or inorganic acid. Acids that can be used in this connection are: hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicyclic acid or benzoic acid.
The compounds according to this invention contain an asymmetric carbon at position 2 of the tetracyclic molecule. By resolving these compounds or a starting product in their synthesis, the optical isomers can also be obtained in a direct way.
iD
1~48539 In the Examples the following nomenclature and numbering has been used:
~ C ~ 11 1, 2, 3, 4-tetrahydro-9H-6 ~ 2 tribenzo (b,d,f)-cyclohepta-~ ~ I triene 7 ~ X ~ 11 X = O or S
6 ~ 12 1, 2, 3, 4-tetrahydro-tribenzo ~ ~ I (b,d,f)-oxepine or -thiepine 7 ~ N ~ 11 6 ~ 12 1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine g~
By way of example the preparation of various starting products is disclosed. The preparation of analogous starting products proceeds in exactly the same way.
Example 1 6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine are added to a suspension of 3.7 g of lithium aluminium hydride in 300 ml of dry ether.
After refluxing for 2 hours 14.8 ml of water are added carefully. The suspension obtained is filtered off and after 11~8539 that the filtrate is dried and e~aporated to dryness to obtain 2-hydroxy-l, , 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine.
2.62 g of the 2-hydroxy compound obtained above is dissolved in 50 ml of benzene whereupon 5 g of phosphorus triiodide is added. The mixture is refluxed for 2 hours. After cooling this mixture ice-water is cautiously added. The organic layer is separated, washed with water and dried. The solvent (benzene) is then evaporated yielding
3.6 g of the oily 2-iodo-compound. This residue is immediately dissolved in 300 ml dimethyl formamide, after which 4 g sodium cyanide is added.
The mixture obtained is heated at 90C for one hour stirring all the time. The reaction-mixture is then poured into 600 ml water and extracted with ether to obtain 2-cyano-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine. The crude nitrile is obtained after evaporation of the ether and immediately used for further reactions.
Example II
1.5 g of 2-cyano-1, 2, 3, 4-tetrahydro-tribenzo ~b,d,f)-oxepine (as prepared in Example I) is suspended in 80 ml diethyleneglycol and 65 ml of an aqueous KOH solution (40%). The mixture is reflu~ed for 5 hours. After cooling the mixture to ambient temperature, it is poured into 450 ml water. The aqueous mixture is extracted with ether to remove non-acidic material. The water-phase is acidified to about pH 3, whereupon the mixture is extracted with ether. The ether extracts are washed, dried and then evaporated, yielding 0.80 g of the crude 2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine.
Example III
l In the manner described in Example II, 2.3 g 2-cyano-1, 2, 3, 4- tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene is hydrolysed ~ 148539 into the corresponding 2-carboxy-compound. Recrystallization from benzene gives 1.2 9 of the pure carboxy-compound, melting point 196-202C, which is then converted into the methyl-, butyl-, benzyl- and phenethyl-ester.
In the same way are prepared:
2-carboxy-7-methoxy-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclohepta-triene.
2-carboxy-7-methoxy-10-chloro-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene.
2-carboxy-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine and the corresponding 7-methoxy compound.
2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-thiepine.
2-carboxy-12-methyl-1,~2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclo-heptatriene.
Example IV
22.50 9 of triethylphosphonoacetate (prepared by means of the Michaelis-Arbuzow reaction) is added dropwise at 20C to a slurry of 50% sodium hydride (4.9 9) in 200 ml of dry 1,2-dimethoxyethane.
After addition the reaction mixture is stirred for 1 hour at room temperature until gas evolution ceased. Then 26 9 of 2-keto-1, 2, 3 , 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene is added slowly at such a rate that the temperature is maintained below 40C. After an additional quarter of an hour the mixture is poured into a large excess of water and the aqueous solution extracted with ether. The ether layer after being dried over sodiumsulphate and evaporated gives 26.0 9 of 2-ethoxycarbonylmethyl -3,4-dihydro-9H-tribenzo (b,d,f)-cycloheptatriene.
Catalytic hydrogenation of 15 9 of this productin methanol ~D g ~1~8539 and palladium~charcoal-catalyst gives the 1, 2, 3, 4-tetrahydro-compound.
In the same manner is prepared 2-ethoxycarbonylmethyl-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo-Cb,d,f) cycloheptatriene.
Example V
10 g of the ethoxycarbonylmethyl-compound obtained in the Example IV is heated in a mixture of 15 g of potassium hydroxide, 10 ml of water and 200 ml of ethanol for 2 hours at boiling temperature.
The mixture is concentrated in vacuo to about 50 ml, diluted with water and acidified to pH 3 with hydrochloric acid. Extraction with benzene and evaporation of the solvent gives 9.5 g of 2-carboxymethyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,t,f)-cycloheptatriene.
In the same manner is prepared:
2-carboxymethyl-9-methyl-1, 2, 3, 4-tetrahydro_H-tribenzo ~b,d,f)-cycloheptatriene.
The mixture obtained is heated at 90C for one hour stirring all the time. The reaction-mixture is then poured into 600 ml water and extracted with ether to obtain 2-cyano-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine. The crude nitrile is obtained after evaporation of the ether and immediately used for further reactions.
Example II
1.5 g of 2-cyano-1, 2, 3, 4-tetrahydro-tribenzo ~b,d,f)-oxepine (as prepared in Example I) is suspended in 80 ml diethyleneglycol and 65 ml of an aqueous KOH solution (40%). The mixture is reflu~ed for 5 hours. After cooling the mixture to ambient temperature, it is poured into 450 ml water. The aqueous mixture is extracted with ether to remove non-acidic material. The water-phase is acidified to about pH 3, whereupon the mixture is extracted with ether. The ether extracts are washed, dried and then evaporated, yielding 0.80 g of the crude 2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine.
Example III
l In the manner described in Example II, 2.3 g 2-cyano-1, 2, 3, 4- tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene is hydrolysed ~ 148539 into the corresponding 2-carboxy-compound. Recrystallization from benzene gives 1.2 9 of the pure carboxy-compound, melting point 196-202C, which is then converted into the methyl-, butyl-, benzyl- and phenethyl-ester.
In the same way are prepared:
2-carboxy-7-methoxy-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclohepta-triene.
2-carboxy-7-methoxy-10-chloro-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene.
2-carboxy-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine and the corresponding 7-methoxy compound.
2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-thiepine.
2-carboxy-12-methyl-1,~2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclo-heptatriene.
Example IV
22.50 9 of triethylphosphonoacetate (prepared by means of the Michaelis-Arbuzow reaction) is added dropwise at 20C to a slurry of 50% sodium hydride (4.9 9) in 200 ml of dry 1,2-dimethoxyethane.
After addition the reaction mixture is stirred for 1 hour at room temperature until gas evolution ceased. Then 26 9 of 2-keto-1, 2, 3 , 4-tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene is added slowly at such a rate that the temperature is maintained below 40C. After an additional quarter of an hour the mixture is poured into a large excess of water and the aqueous solution extracted with ether. The ether layer after being dried over sodiumsulphate and evaporated gives 26.0 9 of 2-ethoxycarbonylmethyl -3,4-dihydro-9H-tribenzo (b,d,f)-cycloheptatriene.
Catalytic hydrogenation of 15 9 of this productin methanol ~D g ~1~8539 and palladium~charcoal-catalyst gives the 1, 2, 3, 4-tetrahydro-compound.
In the same manner is prepared 2-ethoxycarbonylmethyl-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo-Cb,d,f) cycloheptatriene.
Example V
10 g of the ethoxycarbonylmethyl-compound obtained in the Example IV is heated in a mixture of 15 g of potassium hydroxide, 10 ml of water and 200 ml of ethanol for 2 hours at boiling temperature.
The mixture is concentrated in vacuo to about 50 ml, diluted with water and acidified to pH 3 with hydrochloric acid. Extraction with benzene and evaporation of the solvent gives 9.5 g of 2-carboxymethyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,t,f)-cycloheptatriene.
In the same manner is prepared:
2-carboxymethyl-9-methyl-1, 2, 3, 4-tetrahydro_H-tribenzo ~b,d,f)-cycloheptatriene.
Claims (49)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a compound of the general formula XII
or a salt or ester thereof, wherein X stands for oxygen, sulphur, the group or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of l to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11-and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of l to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R7 represents hydrogen or methyl, and n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula XIII
or a corresponding amide, wherein ring A, ring B, n and X are as previously defined; or (b) reacting a corresponding organometallic compound of the formula M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained, or (c) hydrogenating a corresponding 3,4-dihydro compound; and when a free acid of formula I is required hydrolysing a corresponding ester.
or a salt or ester thereof, wherein X stands for oxygen, sulphur, the group or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a halogen having an atomic number not greater than 53, an alkoxy group of l to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11-and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of l to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, R7 represents hydrogen or methyl, and n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula XIII
or a corresponding amide, wherein ring A, ring B, n and X are as previously defined; or (b) reacting a corresponding organometallic compound of the formula M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained, or (c) hydrogenating a corresponding 3,4-dihydro compound; and when a free acid of formula I is required hydrolysing a corresponding ester.
2. A process according to claim 1 in which a free acid of formula I
is esterified to produce a corresponding ester.
is esterified to produce a corresponding ester.
3. A process according to claim 2 in which the ester is a methyl, butyl benzyl or phenethyl ester.
4. A process according to claim 1(a) in which the hydrolysis is effected by reaction with alkali.
5. A process according to claim 1 in which ring A and ring B are unsubstituted or are substituted by chlorine, methoxy or methyl, and X stands for oxygen, sulphur, the group or the group .
6. A process according to claim 1 in which ring A and ring B are unsubstituted, X stands for the group and n is one.
7. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f) cycloheptatriene which comprises hydrolysing 2-cyano-1, 2, 3, 4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene.
8. A process according to claim 7 in which the free acid obtained is converted into the corresponding methyl, butyl, benzyl or phenethyl ester.
9. A process according to claim 1 in which ring A and ring B are un-substituted, X is the group and n is two.
10. A process for the preparation of 2-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene which comprises hydrogenating the corresponding 3,4-dihydro compound.
11. A process according to claim 10 in which the starting material is prepared by reacting 2-keto-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cyclohepta-triene with triethylphosphoroacetate and sodium hydride.
12. A process according to claim 10 in which the ester obtained is hydrolysed to produce 2-carboxymethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene.
13. A compound of the general formula XII as defined in claim 1 whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
14. A compound of the general formula XII given in claim 1 in which ring A, ring B, X and n are as defined in claim 5, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
15. 2-carboxy-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
16. The methyl, butyl, benzyl or phenethyl ester of 2-carboxy-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
17. 2-Ethoxycarbonylmethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
18. 2-Carboxymethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cyclo-heptatriene whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
19. Process for the preparation of a compound of the general formula or a salt or ester thereof, wherein X stands for oxygen or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11-and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula XIII
or a corresponding amide, wherein ring A, ring B, n and X are as previously defined; or (b) reacting a corresponding organometallic compound of the formula M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained, or (c) hydrogenating a corresponding 3,4-dihydro compound; and when a free acid of formula I is required hydrolysing a corresponding ester.
ring A is either unsubstituted or substituted in the 6- or 7-position by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group, ring B is either unsubstituted or substituted in either or both of the 11-and 12- positions by a halogen having an atomic number not greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group, n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula XIII
or a corresponding amide, wherein ring A, ring B, n and X are as previously defined; or (b) reacting a corresponding organometallic compound of the formula M Hal wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and decomposing the organometallic complex so obtained, or (c) hydrogenating a corresponding 3,4-dihydro compound; and when a free acid of formula I is required hydrolysing a corresponding ester.
20. A compound of the general formula as defined in claim 19 whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
21. A process according to claim 19, in which a free acid of formula I
is esterified to produce a corresponding ester.
is esterified to produce a corresponding ester.
22. A process according to claim 21, in which the ester is a methyl, butyl, benzyl or phenethyl ester.
23. A process according to claim 19(a), in which the hydrolysis is effected by reaction with alkali.
24. A process according to claim 19, in which in the starting materials ring A and ring B are unsubstituted or are substituted by chlorine, methoxy or methyl.
25. A process according to claim 19, in which in the starting materials ring A and ring B are unsubstituted, X stands for the group and n is one.
26. A process according to claim 19, in which in the starting materials ring A and ring B are unsubstituted, X stands for the group and n is two.
27. A process according to claim 7, in which the starting material 2-cyano-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene is prepared by reacting 2-iodo-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene with sodium cyanide.
28. A process according to claim 1(c) or 19(c), in which the corresponding 3,4-dihydro compound is prepared by reacting a compound of the general formula Il:
(II) in which X, ring A and ring B are as defined in claim 1 or 19, with a compound represented by the formula Ph3P=CH-B or (EtO)2-P(?O)-CH2-COR' in NaH and a suitable solvent or with a compound represented by the formula BrZn-CH2-COR', wherein Ph stands for an aryl group, B represents a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or hydroxy group and R' stands for an alkoxy group, and if necessary converting the moiety of the product into a carboxyl group or a salt or ester thereof.
(II) in which X, ring A and ring B are as defined in claim 1 or 19, with a compound represented by the formula Ph3P=CH-B or (EtO)2-P(?O)-CH2-COR' in NaH and a suitable solvent or with a compound represented by the formula BrZn-CH2-COR', wherein Ph stands for an aryl group, B represents a carboxyl group, an esterified carboxyl group, an amide group, a cyano group or hydroxy group and R' stands for an alkoxy group, and if necessary converting the moiety of the product into a carboxyl group or a salt or ester thereof.
29. A process according to claim 1(a) or 19(a), in which the compound of the formula XIII is prepared by (1) reducing a compound of the formula II:
(II) in which X, ring A and ring B are as defined in claim 1 or 19, to the corresponding hydroxy compound, (2) converting the hydroxy compound produced of step (1) into a corresponding halide, and (3) reacting the halide thus obtained with an alkali metal cyanide.
(II) in which X, ring A and ring B are as defined in claim 1 or 19, to the corresponding hydroxy compound, (2) converting the hydroxy compound produced of step (1) into a corresponding halide, and (3) reacting the halide thus obtained with an alkali metal cyanide.
30. A process according to claim 1(b) or 19(b), in which the metal is magnesium and the halogen is iodine.
31. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine which comprises hydrolysing 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine.
32. 2-Carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.
33. A process according to claim 31, in which the starting material is prepared by (1) reducing 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine by lithium aluminum hydride to obtain 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, (2) reacting the 2-hydroxy compound obtained in step (1) with phosphorous triiodide to obtain 2-iodo-1,2,3,4-tetrahydrotribenzo(b,d,f)-oxepine, (3) reacting the 2-iodo compound obtained in step (2) with sodium cyanide.
34. A process for the preparation of 2-carboxy-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing 2-cyano-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.
35. 2-Carboxy-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-heptatriene whenever prepared by the process of claim 34 or by an obvious chemical equivalent thereof.
36. A process for the preparation of 2-carboxy-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing 2-cyano-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-triene.
37. 2-Carboxy-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene whenever prepared by the process of claim 36 or by an obvious chemical equivalent thereof.
38. A process for the preparation of 2-carboxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine which comprises hydrolysing 2-cyano-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.
39. 2-Carboxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine whenever prepared by the process of claim 38 or by an obvious chemical equivalent thereof.
40. A process for the preparation of 2-carboxy-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine which comprises hydrolysing 2-cyano-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.
41. 2-Carboxy-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine whenever prepared by the process of claim 40 or by an obvious chemical equivalent thereof.
42. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine which comprises hydrolysing 2-cyano-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine.
43. 2-Carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine whenever prepared by the process of claim 42 or by an obvious chemical equivalent thereof.
44. A process for the preparation of 2-carboxy-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing 2-cyano-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.
45. 2-Carboxy-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene whenever prepared by the process of claim 44 or by an obvious chemical equivalent thereof.
46. A process for the preparation of 2-ethoxycarbonylmethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrogenating the corresponding 3,4-dihydro compound.
47. 2-Ethoxycarbonylmethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene whenever prepared by the process of claim 46 or by an obvious chemical equivalent thereof.
48. A process according to claim 44 in which the ester obtained is hydrolysed to produce 2-carboxymethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.
49. 2-Carboxymethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene whenever prepared by the process of claim 48 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000318927A CA1148539A (en) | 1974-05-15 | 1979-01-02 | Amino-substituted tetracyclic compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA199,996A CA1051877A (en) | 1974-05-15 | 1974-05-15 | Amino-substituted tetracyclic compounds |
| CA000318927A CA1148539A (en) | 1974-05-15 | 1979-01-02 | Amino-substituted tetracyclic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1148539A true CA1148539A (en) | 1983-06-21 |
Family
ID=25667574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000318927A Expired CA1148539A (en) | 1974-05-15 | 1979-01-02 | Amino-substituted tetracyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1148539A (en) |
-
1979
- 1979-01-02 CA CA000318927A patent/CA1148539A/en not_active Expired
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